Monkeypox virus (MPXV) is an orthopoxvirus in the Poxviridae family. The current multinational monkeypox outbreak has now spread to 96 countries that have not historically reported monkeypox, with most cases occurring among gay, bisexual, and other men who have sex with men (1,2). The first monkeypox case in the United States associated with this outbreak was identified in May 2022 in Massachusetts (1); monkeypox has now been reported in all 50 states, the District of Columbia (DC), and one U.S. territory. MPXV is transmitted by close contact with infected persons or animals; infection results in a febrile illness followed by a diffuse vesiculopustular rash and lymphadenopathy. However, illness in the MPXV current Clade II outbreak has differed: the febrile prodrome is frequently absent or mild, and the rash often involves genital, anal, or oral regions (3,4). Although neuroinvasive disease has been previously reported with MPXV infection (5,6), it appears to be rare. This report describes two cases of encephalomyelitis in patients with monkeypox disease that occurred during the current U.S. outbreak. Although neurologic complications of acute MPXV infections are rare, suspected cases should be reported to state, tribal, local, or territorial health departments to improve understanding of the range of clinical manifestations of and treatment options for MPXV infections during the current outbreak.

BACKGROUND: HIV testing efficiency could be improved by focusing on high yield populations and identifying types of health facilities where people with undiagnosed HIV infection are more likely to attend. METHODS: A retrospective cohort analysis of data collected during an integrated TB/HIV active case-finding intervention in Western Kenya. Data were analyzed from health facilities' registers on individuals who reported TB-suggestive symptoms between 1 July and 31 December 2018 and who had an HIV test result within one month following symptom screening. We used logistic regression with general estimating equations adjusting for sub-county level data to identify health facility-level predictors of new HIV diagnoses. RESULTS: Of 11,376 adults with presumptive TB identified in 143 health facilities, 1038 (9%) tested HIV positive. The median HIV positivity per health facility was 6% (IQR = 2-15%). Patients with TB symptoms were over three times as likely to have a new HIV diagnosis in private not-for-profit facilities compared to those in government facilities (adjusted odds ratio (aOR) 3.40; 95% CI = 1.96-5.90). Patients tested in hospitals were over two times as likely to have a new HIV diagnosis as those tested in smaller facilities (i.e., health centers and dispensaries) (aOR 2.26; 95% CI = 1.60-3.21). CONCLUSION: Individuals with presumptive TB who attended larger health facilities and private not-for-profit facilities had a higher likelihood of being newly diagnosed with HIV. Strengthening HIV services at these facilities and outreach to populations that use them could help to close the HIV diagnosis gap.

Talaromycosis (penicilliosis) is an invasive mycosis that is endemic in tropical and subtropical Asia. Talaromycosis primarily affects individuals with advanced HIV disease and other immunosuppressive conditions, and the disease disproportionally affects people in low-income and middle-income countries, particularly agricultural workers in rural areas during their most economically productive years. Approximately 17 300 talaromycosis cases and 4900 associated deaths occur annually. Talaromycosis is highly associated with the tropical monsoon season, when flooding and cyclones can exacerbate the poverty-inducing potential of the disease. Talaromycosis can present as localised or disseminated disease, the latter causing cutaneous lesions that are disfiguring and stigmatising. Despite up to a third of diagnosed cases resulting in death, talaromycosis has received little attention and investment from regional and global funders, policy makers, researchers, and industry. Diagnostic and treatment modalities remain extremely insufficient, however control of talaromycosis is feasible with known public health strategies. This Viewpoint is a global call for talaromycosis to be recognised as a neglected tropical disease to alleviate its impact on susceptible populations.

OBJECTIVES: Describe the causes of death among infants and children <5 years stratified by HIV status. DESIGN: Cross-sectional analysis of causes of death ascertained through minimally invasive tissue sampling (MITS) in the Kenya Child Health and Mortality Prevention Surveillance site. METHODS: We included decedents aged 28 days to <5 years, whose death was reported within 36 hours, underwent MITS, and had HIV test results and causes of death determined. MITS specimens were tested using Taqman Array Cards, culture, cytology, histopathology and immunohistochemistry and HIV polymerase chain reaction. A panel evaluated epidemiologic, clinical, verbal autopsy and laboratory data to assign causes of death using ICD10 guidelines. Causes of death and etiological agents were stratified by HIV status. RESULTS: Of 176 included decedents, 14% (n = 25) were HIV-infected, median viral load was 112,205 copies per milliliter (interquartile range [IQR] = 9,349-2,670,143). HIV-disease (96%; n = 24) and malnutrition (23%; n = 34) were the leading underlying causes of death in HIV-infected and HIV-uninfected decedents, respectively. Malnutrition was more frequent in the causal chain of HIV-infected (56%; n = 14) than HIV-uninfected decedents (31%; n = 49) (p-value = 0.03). Viral pneumonia was twice as common in HIV-infected (50%; n = 9) than HIV-uninfected decedents (22%; n = 7) (p-value = 0.04). CONCLUSION: Nearly all HIV-infected decedents' underlying cause of death was HIV disease which was associated with malnutrition. Our findings underscore the need for strengthening early identification and management of HIV-infected children. Prevention, early diagnosis and treatment of malnutrition could be instrumental in improving the survival of HIV-infected and HIV-uninfected children.

Tenofovir disoproxil fumarate (TDF) is one of the nucleotide analogs capable of inhibiting the reverse transcriptase (RT) activity of HIV and hepatitis B virus (HBV). There is no known HBV resistance to TDF. However, detectable variation in duration of HBV persistence in patients on TDF therapy suggests the existence of genetic mechanisms of on-drug persistence that reduce TDF efficacy for some HBV strains without affording actual resistance. Here, the whole genome of intra-host HBV variants (N = 1,288) was sequenced from patients with rapid (RR, N = 5) and slow response (SR, N = 5) to TDF. Association of HBV genomic and protein polymorphic sites to RR and SR was assessed using phylogenetic analysis and Bayesian network methods. We show that, in difference to resistance to nucleotide analogs, which is mainly associated with few specific mutations in RT, the HBV on-TDF persistence is defined by genetic variations across the entire HBV genome. Analysis of the inferred 3D-structures indicates no difference in affinity of TDF binding by RT encoded by intra-host HBV variants that rapidly decline or persist in presence of TDF. This finding suggests that effectiveness of TDF recognition and binding does not contribute significantly to on-drug persistence. Differences in patterns of genetic associations to TDF response between HBV genotypes B and C and lack of a single pattern of mutations among intra-host variants sensitive to TDF indicate a complex genetic encoding of the trait. We hypothesize that there are many genetic mechanisms of on-drug persistence, which are differentially available to HBV strains. These pervasive mechanisms are insufficient to prevent viral inhibition completely but may contribute significantly to robustness of actual resistance. On-drug persistence may reduce the overall effectiveness of therapy and should be considered for development of more potent drugs.

OBJECTIVE: To compare the prevalence of tuberculosis infection and disease in household contacts of patients with bacteriologically confirmed tuberculosis disease and contacts of non-bacteriologically confirmed disease in western Kenya. METHODS: We enrolled newly diagnosed index patients and their household contacts from March 2014 to June 2016. All contacts were evaluated with a symptom questionnaire, tuberculin skin test (TST), and HIV test. Clinical evaluation and sputum testing were performed for those with symptoms, positive TST result, or HIV infection. RESULTS: We enrolled 1155 contacts of 330 index patients with bacteriologically confirmed tuberculosis and 192 contacts of 55 index patients with non-bacteriologically confirmed tuberculosis. 3.5% of contacts of patients with bacteriologically confirmed tuberculosis were diagnosed with tuberculosis, whereas no contacts of index patients with non-bacteriologically confirmed tuberculosis were. Of those diagnosed with tuberculosis disease, 58.5% reported symptoms, 34.1% reported no symptoms but had positive TST results, and 7.3% had neither symptoms nor positive TST but were HIV-positive. Among 872 contacts with a TST result, 50.9% of contacts of index patients with bacteriologically confirmed tuberculosis and 41.0% of contacts of index patients with non-bacteriologically confirmed tuberculosis had a positive result (prevalence ratio = 1.16, 95% confidence interval 0.92-1.48). CONCLUSION: In a high-burden setting, tuberculosis disease was more prevalent among contacts of patients with bacteriologically confirmed tuberculosis than contacts of patients with non-bacteriologically confirmed disease. TST was feasible to perform and helped to detect cases that would have been missed had only symptomatic contacts been evaluated.

OBJECTIVE: To evaluate the utility of a broad and non-specific symptom screen for identifying people with undiagnosed HIV infection. DESIGN: Secondary analysis of operational data collected during implementation of a cluster-randomized trial for tuberculosis case detection. METHODS: As part of the trial, adults reporting cough, fever, night sweats, weight loss, or difficulty breathing of any duration in the past month were identified in health facilities and community-based mobile screening units in western Kenya. Adults reporting any symptom were offered HIV testing. We analysed the HIV testing data from this study, using modified Poisson regression to identify predictors of new HIV diagnoses among adults with symptoms and initially unknown HIV status. RESULTS: We identified 3,818 symptomatic adults, referred 1424 (37%) for testing, of whom 1065 (75%) accepted, and 107 (10%) were newly diagnosed with HIV. The prevalence of new HIV diagnoses was 21% (95% CI: 17-25%) among those tested in health facilities and 5% (95% CI 4-7%) among those tested in mobile units. More men were diagnosed with HIV than women despite fewer men being screened. People who reported 4-5 symptoms were over twice as likely to be diagnosed with HIV compared to those reporting 1-3 symptoms (adjusted prevalence ratio [aPR] in health facilities = 2.58, 95% CI, 1.65-4.05; aPR in mobile units = 2.63, 95% CI, 1.37-5.03). CONCLUSION: We observed a high yield of new HIV diagnoses among adults identified by active application of a broad symptom screen. Integrated tuberculosis and HIV screening using could help close the detection gap for both conditions.

SETTING: Efficient tuberculosis (TB) active case-finding strategies are important in settings with high TB burdens and limited resources, such as those in western Kenya. OBJECTIVE: To guide efforts to optimize screening efficiency, we identified the predictors of TB among people screened in health facilities and communities. DESIGN: During February 2015-June 2016, adults aged >/=15 years reporting any TB symptom were identified in health facilities and community mobile screening units, and evaluated for TB. We assessed the predictors of TB using a modified Poisson regression with generalized estimating equations to account for clustering according to screening site. RESULTS: TB was diagnosed in 484 (20.3%) of 2394 symptomatic adults in health facilities and 39 (3.4%) of 1424 in communities. In health facilities, >10% of symptomatic adults in all demographic groups had TB, and no predictors were associated with a >/=2-fold increased risk. In communities, the independent predictors of TB were male sex (adjusted prevalence ratio [aPR] = 4.26, 95%CI 2.43-7.45), HIV infection (aPR 2.37, 95%CI 1.18-4.77), and household TB contact in the last 2 years (aPR 2.84, 95%CI 1.62-4.96). CONCLUSION: Our findings support the notion of general TB screening in health facilities and evaluation of the adult household contacts of TB patients.

OBJECTIVE: To evaluate the utility of a broad and non-specific symptom screen for identifying people with undiagnosed HIV infection. DESIGN: Secondary analysis of operational data collected during implementation of a cluster-randomized trial for tuberculosis case detection. METHODS: As part of the trial, adults reporting cough, fever, night sweats, weight loss, or difficulty breathing of any duration in the past month were identified in health facilities and community-based mobile screening units in western Kenya. Adults reporting any symptom were offered HIV testing. We analysed the HIV testing data from this study, using modified Poisson regression to identify predictors of new HIV diagnoses among adults with symptoms and initially unknown HIV status. RESULTS: We identified 3,818 symptomatic adults, referred 1424 (37%) for testing, of whom 1065 (75%) accepted, and 107 (10%) were newly diagnosed with HIV. The prevalence of new HIV diagnoses was 21% (95% CI: 17-25%) among those tested in health facilities and 5% (95% CI 4-7%) among those tested in mobile units. More men were diagnosed with HIV than women despite fewer men being screened. People who reported 4-5 symptoms were over twice as likely to be diagnosed with HIV compared to those reporting 1-3 symptoms (adjusted prevalence ratio [aPR] in health facilities = 2.58, 95% CI, 1.65-4.05; aPR in mobile units = 2.63, 95% CI, 1.37-5.03). CONCLUSION: We observed a high yield of new HIV diagnoses among adults identified by active application of a broad symptom screen. Integrated tuberculosis and HIV screening using could help close the detection gap for both conditions.

Setting: Although Kenya has a high burden of tuberculosis (TB), only 46% of cases were diagnosed in 2016. Objective: To identify strategies for increasing attendance at community-based mobile screening units. Design: We analysed operational data from a cluster-randomised trial, which included community-based mobile screening implemented during February 2015-April 2016. Community health volunteers (CHVs) recruited individuals with symptoms from the community, who were offered testing for human immunodeficiency virus (HIV) and sputum collection for Xpert((R)) MTB/RIF testing. We compared attendance across different mobile unit sites using Wilcoxon rank-sum test. Results: A total of 1424 adults with symptoms were screened at 25 mobile unit sites. The median total attendance among sites was 54 (range 6-134, interquartile range [IQR] 24-84). The median yields of TB diagnoses and new HIV diagnoses were respectively 2.4% (range 0.0-16.7, IQR 0.0-5.3) and 2.5% (range 0.0-33.3, IQR 1.2-4.2). Attendance at urban sites was variable; attendance at rural sites where CHVs were paid a daily minimum wage was significantly higher than at rural sites where CHVs were paid a nominal monthly stipend (P < 0.001). Conclusion: Mobile units were most effective and efficient when implemented as a single event with community health workers who are paid a daily wage.

The genomic sequences of two enterovirus C109 isolates (EV-C109 USA/FL/2016-21003 and EV-C109 USA/FL/2016-21002) were obtained during two separate case investigations of respiratory disease in two children. This marks the first description of EV-C109 genomes in the United States. Copyright © 2018 Kyoui et al.

BACKGROUND: HIV is a major driver of the tuberculosis epidemic in sub-Saharan Africa. The population-level impact of antiretroviral therapy (ART) scale-up on tuberculosis rates in this region has not been well studied. We conducted a descriptive analysis to examine evidence of population-level effect of ART on tuberculosis by comparing trends in estimated tuberculosis notification rates, by HIV status, for countries in sub-Saharan Africa. METHODS: We estimated annual tuberculosis notification rates, stratified by HIV status during 2010-2015 using data from WHO, the Joint United Nations Programme on HIV/AIDS, and the United Nations Population Division. Countries were included in this analysis if they had >/=4 years of HIV prevalence estimates and >/= 75% of tuberculosis patients with known HIV status. We compared tuberculosis notification rates among people living with HIV (PLHIV) and people without HIV via Wilcoxon rank sum test. RESULTS: Among 23 included countries, the median annual average change in tuberculosis notification rates among PLHIV during 2010-2015 was -5.7% (IQR -6.9 to -1.7%), compared to a median change of -2.3% (IQR -4.2 to -0.1%) among people without HIV (p-value = 0.0099). Among 11 countries with higher ART coverage, the median annual average change in TB notification rates among PLHIV was -6.8% (IQR -7.6 to -5.7%) compared to a median change of -2.1% (IQR -6.0 to 0.7%) for PLHIV in 12 countries with lower ART coverage (p = 0.0106). CONCLUSION: Tuberculosis notification rates declined more among PLHIV than people without HIV, and have declined more in countries with higher ART coverage. These results are consistent with a population-level effect of ART on decreasing TB incidence among PLHIV. To further reduce TB incidence among PLHIV, additional scale-up of ART as well as greater use of isoniazid preventive therapy and active case-finding will be necessary.

Animal models suggest that gut microbiota contribute to obesity; however, a consistent taxonomic signature of obesity has yet to be identified in humans. We examined whether a taxonomic signature of obesity is present across two independent study populations. We assessed gut microbiome from stool for 599 adults, by 16S rRNA gene sequencing. We compared gut microbiome diversity, overall composition, and individual taxon abundance for obese (BMI >/= 30 kg/m(2)), overweight (25 </= BMI < 30), and healthy-weight participants (18.5 </= BMI < 25). We found that gut species richness was reduced (p = 0.04), and overall composition altered (p = 0.04), in obese (but not overweight) compared to healthy-weight participants. Obesity was characterized by increased abundance of class Bacilli and its families Streptococcaceae and Lactobacillaceae, and decreased abundance of several groups within class Clostridia, including Christensenellaceae, Clostridiaceae, and Dehalobacteriaceae (q < 0.05). These findings were consistent across two independent study populations. When random forest models were trained on one population and tested on the other as well as a previously published dataset, accuracy of obesity prediction was good (~70%). Our large study identified a strong and consistent taxonomic signature of obesity. Though our study is cross-sectional and causality cannot be determined, identification of microbes associated with obesity can potentially provide targets for obesity prevention and treatment.

BACKGROUND: Mortality from TB continues to be a global public health challenge. TB ranks alongside Human Immunodeficiency Virus (HIV) as the leading infectious causes of death globally. HIV is a major driver of TB related morbidity and mortality while TB is the leading cause of mortality among people living with HIV/AIDS. We sought to determine excess mortality associated with HIV and the effect of antiretroviral therapy on reducing mortality among tuberculosis patients in Kenya. METHODS: We conducted a retrospective analysis of Kenya national tuberculosis program data of patients enrolled from 2013 through 2014. We used direct standardization to obtain standardized mortality ratios for tuberculosis patients compared with the general population. We calculated the population attributable fraction of tuberculosis deaths due to HIV based on the standardized mortality ratio for deaths among TB patients with HIV compared to TB patients without HIV. We used Cox proportional hazards regression for assessing risk factors for mortality. RESULTS: Of 162,014 patients included in the analysis, 6% died. Mortality was 10.6 (95% CI: 10.4-10.8) times higher among TB patients than the general population; 42% of deaths were attributable to HIV infection. Patients with HIV who were not receiving ART had an over four-fold risk of death compared to patients without HIV (aHR = 4.2, 95% CI 3.9-4.6). In contrast, patients with HIV who were receiving ART had only 2.6 times the risk of death (aHR = 2.6, 95% CI 2.5-2.7). CONCLUSION: HIV was a significant contributor to TB-associated deaths in Kenya. Mortality among HIV-infected individuals was higher among those not on ART than those on ART. Early initiation of ART among HIV infected people (a "test and treat" approach) should further reduce TB-associated deaths.

BACKGROUND: Colorectal cancer is a heterogeneous disease arising from at least two precursors-the conventional adenoma (CA) and the serrated polyp. We and others have previously shown a relationship between the human gut microbiota and colorectal cancer; however, its relationship to the different early precursors of colorectal cancer is understudied. We tested, for the first time, the relationship of the gut microbiota to specific colorectal polyp types. RESULTS: Gut microbiota were assessed in 540 colonoscopy-screened adults by 16S rRNA gene sequencing of stool samples. Participants were categorized as CA cases (n = 144), serrated polyp cases (n = 73), or polyp-free controls (n = 323). CA cases were further classified as proximal (n = 87) or distal (n = 55) and as non-advanced (n = 121) or advanced (n = 22). Serrated polyp cases were further classified as hyperplastic polyp (HP; n = 40) or sessile serrated adenoma (SSA; n = 33). We compared gut microbiota diversity, overall composition, and normalized taxon abundance among these groups. CA cases had lower species richness in stool than controls (p = 0.03); in particular, this association was strongest for advanced CA cases (p = 0.004). In relation to overall microbiota composition, only distal or advanced CA cases differed significantly from controls (p = 0.02 and p = 0.002). In taxon-based analysis, stool of CA cases was depleted in a network of Clostridia operational taxonomic units from families Ruminococcaceae, Clostridiaceae, and Lachnospiraceae, and enriched in the classes Bacilli and Gammaproteobacteria, order Enterobacteriales, and genera Actinomyces and Streptococcus (all q < 0.10). SSA and HP cases did not differ in diversity or composition from controls, though sample size for these groups was small. Few taxa were differentially abundant between HP cases or SSA cases and controls; among them, class Erysipelotrichi was depleted in SSA cases. CONCLUSIONS: Our results indicate that gut microbes may play a role in the early stages of colorectal carcinogenesis through the development of CAs. Findings may have implications for developing colorectal cancer prevention therapies targeting early microbial drivers of colorectal carcinogenesis.

We thank Hong-min et al for their interest in our study [1, 2]. They request clarification of the exclusion criteria of studies with fewer than 5 household contacts. We set this minimum a priori in order to avoid bias from very small studies that are likely to have poor accuracy and precision in measuring the outcomes of interest, namely, prevalence of tuberculosis disease and latent tuberculosis infection among household contacts. Our rationale was to prevent such small studies from having undue influence on estimation of overall prevalence based on random effects models. Although there may be a concern for bias in excluding small studies, this criterion applied to only 2 otherwise eligible studies [3, 4] that reported evaluation of 2 and 3 contacts of index patients with drug-resistant tuberculosis. Hong-min et al also suggest that including studies with a single source case could introduce significant heterogeneity and publication bias. While we agree such studies could introduce heterogeneity, we considered that including them reduces bias because studies from low-burden multidrug-resistant tuberculosis settings could be included without affecting the precision of outcome measures. | | A formal evaluation of the quality of the included studies using the suggested scales was not conducted. However, each study was eligible for inclusion only if there were data of sufficient quality and completeness to measure the outcomes of interest, as noted above, prevalence of tuberculosis disease and latent tuberculosis infection among household contacts. The studies we included in our analysis were predominantly cross-sectional. Hong-min et al suggest use of the Newcastle-Ottawa scale or Downs and Black instrument, which are intended for evaluating case-control or cohort designs. One alternative might have been to devise our own quality index (eg, assigning quality “points” to studies that use a standard evaluation protocol). Such a scale would not be considered a validated tool but, nonetheless, might have helped readers interpret our results.

In 2016, the order Mononegavirales was emended through the addition of two new families (Mymonaviridae and Sunviridae), the elevation of the paramyxoviral subfamily Pneumovirinae to family status (Pneumoviridae), the addition of five free-floating genera (Anphevirus, Arlivirus, Chengtivirus, Crustavirus, and Wastrivirus), and several other changes at the genus and species levels. This article presents the updated taxonomy of the order Mononegavirales as now accepted by the International Committee on Taxonomy of Viruses (ICTV).

Tuberculosis is an infectious disease that may result from recent transmission or from an infection acquired many years in the past; there is no diagnostic test to distinguish the two causes. Cases resulting from recent transmission are particularly concerning from a public health standpoint. To describe recent tuberculosis transmission in the United States, we used a field-validated plausible source-case method to estimate cases likely resulting from recent transmission during January 2011-September 2014. We classified cases as resulting from either limited or extensive recent transmission based on transmission cluster size. We used logistic regression to analyze patient characteristics associated with recent transmission. Of 26,586 genotyped cases, 14% were attributable to recent transmission, 39% of which were attributable to extensive recent transmission. The burden of cases attributed to recent transmission was geographically heterogeneous and poorly predicted by tuberculosis incidence. Extensive recent transmission was positively associated with American Indian/Alaska Native (adjusted prevalence ratio [aPR] = 3.6 (95% confidence interval [CI] 2.9-4.4), Native Hawaiian/Pacific Islander (aPR = 3.2, 95% CI 2.3-4.5), and black (aPR = 3.0, 95% CI 2.6-3.5) race, and homelessness (aPR = 2.3, 95% CI 2.0-2.5). Extensive recent transmission was negatively associated with foreign birth (aPR = 0.2, 95% CI 0.2-0.2). Tuberculosis control efforts should prioritize reducing transmission among higher-risk populations.

BACKGROUND: For treating multidrug-resistant tuberculosis (MDR TB), the World Health Organization (WHO) recommends a regimen of at least four second-line drugs that are likely to be effective as well as pyrazinamide. WHO guidelines indicate only marginal benefit for regimens based directly on drug susceptibility testing (DST) results. Recent evidence from isolated cohorts suggests that regimens containing more drugs may be beneficial, and that DST results are predictive of regimen effectiveness. The objective of our study was to gain insight into how regimen design affects treatment response by analyzing the association between time to sputum culture conversion and both the number of potentially effective drugs included in a regimen and the DST results of the drugs in the regimen. METHODS AND FINDINGS: We analyzed data from the Preserving Effective Tuberculosis Treatment Study (PETTS), a prospective observational study of 1,659 adults treated for MDR TB during 2005-2010 in nine countries: Estonia, Latvia, Peru, Philippines, Russian Federation, South Africa, South Korea, Thailand, and Taiwan. For all patients, monthly sputum samples were collected, and DST was performed on baseline isolates at the US Centers for Disease Control and Prevention. We included 1,137 patients in our analysis based on their having known baseline DST results for at least fluoroquinolones and second-line injectable drugs, and not having extensively drug-resistant TB. These patients were followed for a median of 20 mo (interquartile range 16-23 mo) after MDR TB treatment initiation. The primary outcome of interest was initial sputum culture conversion. We used Cox proportional hazards regression, stratifying by country to control for setting-associated confounders, and adjusting for the number of drugs to which patients' baseline isolates were resistant, baseline resistance pattern, previous treatment history, sputum smear result, and extent of disease on chest radiograph. In multivariable analysis, receiving an average of at least six potentially effective drugs (defined as drugs without a DST result indicating resistance) per day was associated with a 36% greater likelihood of sputum culture conversion than receiving an average of at least five but fewer than six potentially effective drugs per day (adjusted hazard ratio [aHR] 1.36, 95% CI 1.09-1.69). Inclusion of pyrazinamide (aHR 2.00, 95% CI 1.65-2.41) or more drugs to which baseline DST indicated susceptibility (aHR 1.65, 95% CI 1.48-1.84, per drug) in regimens was associated with greater increases in the likelihood of sputum culture conversion than including more drugs to which baseline DST indicated resistance (aHR 1.33, 95% CI 1.18-1.51, per drug). Including in the regimen more drugs for which DST was not performed was beneficial only if a minimum of three effective drugs was present in the regimen (aHR 1.39, 95% CI 1.09-1.76, per drug when three effective drugs present in regimen). The main limitation of this analysis is that it is based on observational data, not a randomized trial, and drug regimens varied across sites. However, PETTS was a uniquely large and rigorous observational study in terms of both the number of patients enrolled and the standardization of laboratory testing. Other limitations include the assumption of equivalent efficacy across drugs in a category, incomplete data on adherence, and the fact that the analysis considers only initial sputum culture conversion, not reversion or long-term relapse. CONCLUSIONS: MDR TB regimens including more potentially effective drugs than the minimum of five currently recommended by WHO may encourage improved response to treatment in patients with MDR TB. Rapid access to high-quality DST results could facilitate the design of more effective individualized regimens. Randomized controlled trials are necessary to confirm whether individualized regimens with more than five drugs can indeed achieve better cure rates than current recommended regimens.

OBJECTIVE: To compare trends in direct annual risk of tuberculous infection (ARTI) during 1991-2005 in relation to tuberculosis (TB) incidence and to indirect estimates of ARTI derived from the prevalence of tuberculin skin test (TST) positivity in schoolchildren in Orel Oblast, Russia. DESIGN: In 2005, we abstracted annual TST results and vaccination histories from a representative sample of schoolchildren in Orel Oblast, Russia, where bacille Calmette-Guerin (BCG) vaccination and annual TST of children are nearly universal. We calculated direct ARTI based on the percentage of children tested with TST conversions each year, excluding conversions following BCG vaccination. RESULTS: We analysed records from 13 206 children, with a median of 10 recorded TST results per child. The ARTI increased from 0.2% in 1991 to 1.6% in 2000, paralleling trends in TB incidence. Similar results were observed when the ARTI was estimated based on prevalence of infection among children aged 3-5 years using a 12 mm cut-off to define TST positivity. Results differed substantially when 10 or 15 mm cut-offs were used or when prevalence was determined among children aged 6-8 years. CONCLUSION: ARTI measured through TST conversion increased as TB incidence increased in Orel Oblast. ARTI measured through serial TSTs can thus provide an indicator of changing trends in TB incidence.

BACKGROUND: In Kenya, the comparative incidences of tuberculosis among persons with and without HIV have not been described, and the differential impact of public health interventions on tuberculosis incidence in the two groups is unknown. METHODS: We estimated annual tuberculosis incidence stratified by HIV status during 2006-2012 based on the numbers of reported tuberculosis patients with and without HIV infection, the prevalence of HIV infection in the general population, and the total population. We also made crude estimates of annual tuberculosis incidence stratified by HIV status during 1998-2012 by assuming a constant ratio of HIV prevalence among tuberculosis patients compared to the general population. RESULTS: Tuberculosis incidence among both adults with HIV and adults without HIV increased during 1998-2004 then remained relatively stable until 2007. During 2007-2012, tuberculosis incidence declined by 28-44% among adults with HIV and by 11-26% among adults without HIV, concurrent with an increase in antiretroviral therapy uptake. In 2012, tuberculosis incidence among adults with HIV (1,839-1,936 cases/100,000 population) was still eight times as high as among adults without HIV (231-238 cases/100,000 population), and approximately one third of tuberculosis cases were attributable to HIV. CONCLUSIONS: Although tuberculosis incidence has declined among adults with and without HIV, the persistent high incidence of tuberculosis among those with HIV and the disparity between the two groups are concerning. Early diagnosis of HIV, early initiation of antiretroviral therapy, regular screening for tuberculosis, and isoniazid preventive therapy among persons with HIV, as well as tuberculosis control in the general population, are required to address these issues.

In 2013, a total of 9,588 new tuberculosis (TB) cases were reported in the United States, with an incidence rate of 3.0 cases per 100,000 population, a decrease of 4.2% from 2012. This report summarizes provisional TB surveillance data reported to CDC in 2013. Although case counts and incidence rates continue to decline, certain populations are disproportionately affected. The TB incidence rate among foreign-born persons in 2013 was approximately 13 times greater than the incidence rate among U.S.-born persons, and the proportion of TB cases occurring in foreign-born persons continues to increase, reaching 64.6% in 2013. Racial/ethnic disparities in TB incidence persist, with TB rates among non-Hispanic Asians almost 26 times greater than among non-Hispanic whites. Four states (California, Texas, New York, and Florida), home to approximately one third of the U.S. population, accounted for approximately half the TB cases reported in 2013. The proportion of TB cases occurring in these four states increased from 49.9% in 2012 to 51.3% in 2013. Continued progress toward TB elimination in the United States will require focused TB control efforts among populations and in geographic areas with disproportionate burdens of TB.

BACKGROUND: Development of resistance to antituberculosis drugs during treatment (i.e., acquired resistance) can lead to emergence of resistant strains and consequent poor clinical outcomes. However, it is unknown whether Mycobacterium tuberculosis complex species and lineage affects the likelihood of acquired resistance. METHODS: We analyzed data from the U.S. National Tuberculosis Surveillance System and National Tuberculosis Genotyping Service for tuberculosis cases during 2004-2011 with assigned species and lineage and both initial and final drug susceptibility test results. We determined univariate associations between species and lineage of Mycobacterium tuberculosis complex bacteria and acquired resistance to isoniazid, rifamycins, fluoroquinolones, and second-line injectables. We used Poisson regression with backward elimination to generate multivariable models for acquired resistance to isoniazid and rifamycins. RESULTS: M. bovis was independently associated with acquired resistance to isoniazid (adjusted prevalence ratio = 8.46, 95% CI 2.96-24.14) adjusting for HIV status, and with acquired resistance to rifamycins (adjusted prevalence ratio = 4.53, 95% CI 1.29-15.90) adjusting for homelessness, HIV status, initial resistance to isoniazid, site of disease, and administration of therapy. East Asian lineage was associated with acquired resistance to fluoroquinolones (prevalence ratio = 6.10, 95% CI 1.56-23.83). CONCLUSIONS: We found an association between mycobacterial species and lineage and acquired drug resistance using U.S. surveillance data. Prospective clinical studies are needed to determine the clinical significance of these findings, including whether rapid genotyping of isolates at the outset of treatment may benefit patient management.

The Kokobera virus group comprises mosquito-borne flaviviruses that cluster together phylogenetically. These viruses are unique to Australia and Papua New Guinea, and have been associated with a mild polyarticular disease in humans. Recent isolation of genetically diverse viruses within this group has prompted analysis of their genetic and phenotypic relationships. Phylogenetic analysis based on complete ORF, the envelope gene or the NS5/3' untranslated region supported the separation of the group into distinct species: Kokobera virus (KOKV), Stratford virus, New Mapoon virus, MK7979 and TS5273. Virulence studies in 3-week-old mice also provided the first evidence that a member of the KOKV group (MK7979) was neuroinvasive after intraperitoneal inoculation. In this context, our recent detection of KOKV group-specific antibodies in horses in the field suggests that these viruses should be considered in the epidemiology of flavivirus encephalitis in Australia.

OBJECTIVE: To report the impact of the release of the 2002 American Society for Colposcopy and Cervical Pathology guidelines on the management of abnormal cytological findings on time to diagnosis of cervical cancer in an insured population. METHODS: This retrospective study identified women with cervical cancer (invasive and carcinoma in situ) through commercially insured administrative claims data. The cervical cancer case definition required a claim for cervical cancer and a claim with a diagnostic procedure (colposcopy, conization, biopsy, or hysterectomy). Time to diagnosis was defined as days between the initial Pap screening and the diagnostic procedure. RESULTS: Between 1999 and 2004, there were 3,325 women aged 18 to 64 years who met the case definition for cervical cancer. Median time to diagnosis decreased from 42 days (interquartile range = 23-93 d) to 36.5 days (interquartile range = 20.5-80 d) for women with invasive cancer after the guideline change. The number of follow-up Pap screenings before biopsy also decreased (p = .0067). Among women with carcinoma in situ whose initial Pap screening was completed by a family practice clinician, time to diagnosis was projected to be more than 9 days longer compared with those whose screening was performed by a gynecologist. CONCLUSIONS: The 2002 American Society for Colposcopy and Cervical Pathology guidelines for the management of abnormal cytological findings seem to have had a positive impact on the time to diagnosis and Pap screening use before biopsy for women diagnosed with cervical cancer.