Last data update: May 13, 2024. (Total: 46773 publications since 2009)
Records 1-30 (of 63 Records) |
Query Trace: Savage H[original query] |
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U. S. federal perspective on critical research issues in nanoEHS
Carter J , Bjorkland R , Boyes WK , Geraci C , Hackley VA , Howard J , Kennedy A , Linkov I , Matheson J , Mortensen H , Muianga C , Petersen EJ , Savage N , Schulte P , Standridge S , Thomas T , Trump B , Nadadur S . Environ Sci Nano 2023 This article discusses critical issues and opportunities going forward in nanotechnology environmental, health, and safety (nanoEHS) research from the perspective of Federal Government Agency participants in the United States (U.S.) National Nanotechnology Initiative (NNI) interagency Nanotechnology Environmental and Health Implications Working Group (NEHI). NEHI is responsible for coordination of Federal Science Agency nanoEHS research. As participants in NEHI, we examine these critical issues from an integrated, transdisciplinary perspective, noting examples of impactful research efforts that are advancing knowledge in these areas. Major themes identified include detection, measurement, and characterization of real-world nanomaterial exposures, understanding the biological transformation of nanomaterials and their potential (eco) toxicological implications, understanding the landscape of nanotechnology-enabled products in commerce, and advancing the EHS knowledge infrastructure related to nanomaterials and nanotechnology. Significant investments in nanoEHS research over two decades have led to establishment of a unique and diverse multidisciplinary, multisector community of practice. These investments must be leveraged and adapted not only to future nanotechnology, but also to use as a model for accelerating acquisition of safe and reliable risk information for tomorrow's emerging technologies for a more sustainable and competitive world. © 2023 The Royal Society of Chemistry. |
Availability and content of clinical guidance for tobacco use and dependence treatment - United States, 2000-2019
VanFrank B , Uhd J , Savage TR , Shah JR , Twentyman E . Prev Med 2022 164 107276 Evidence-based treatments for tobacco use and dependence can increase cessation success but remain underutilized. Health professional societies and voluntary health organizations (advising organizations) are uniquely positioned to influence the delivery of cessation treatments by providing clinical guidance for healthcare providers. This study aimed to review the guidance produced by these organizations for content and consistency with current evidence. Documents discussing healthcare providers' role in treatment of tobacco use and dependence produced by US-based advising organizations between 2000 and 2019 were identified in both peer-reviewed and grey (i.e., informally or non-commercially published) literature. Extraction of variables, defined in terms of healthcare provider role and endorsement of specific treatment(s), was completed by two independent reviewers. Review of 38 identified documents sponsored by 57 unique advising organizations revealed deficits in the direction of comprehensive care and incorporation of the most recent evidence for treatment of tobacco use and dependence. Documents endorsed: screening (74%), pharmacotherapy (68%), counseling (89%), or follow-up (37%). Few documents endorsed more recent evidence-based treatments including combination nicotine replacement therapy (18%), and text- (11%) and web-based (11%) interventions. Advising organizations have opportunities to address identified gaps and enhance clinical guidance to contribute toward expanding the provision of comprehensive tobacco cessation support. |
Laboratory and field evaluations of a commercially available real-time loop-mediated isothermal amplification assay for the detection of West Nile virus in mosquito pools
Burkhalter KL , O'Keefe M , Holbert-Watson Z , Green T , Savage HM , Markowski DM . J Am Mosq Control Assoc 2021 37 (4) 256-262 Although the specific cDNA amplification mechanisms of reverse-transcriptase polymerase chain reaction (RT-PCR) and RT loop-mediated isothermal amplification (RT-LAMP) are very different, both molecular assays serve as options to detect arboviral RNA in mosquito pools. Like RT-PCR, RT-LAMP uses a reverse transcription step to synthesize complementary DNA (cDNA) from an RNA template and then uses target-specific primers to amplify cDNA to detectable levels in a single-tube reaction. Using laboratory-generated West Nile virus (WNV) samples and field-collected mosquito pools, we evaluated the sensitivity and specificity of a commercially available WNV real-time RT-LAMP assay (Pro-AmpRT™ WNV; Pro-Lab Diagnostics, Inc., Round Rock, Texas) and compared the results to a validated real-time RT-PCR assay. Laboratory generated virus stock samples containing ≥ 2.3 log10 plaque-forming units (PFU)/ml and intrathoracically inoculated mosquitoes containing ≥ 2.4 log10 PFU/ml produced positive results in the Pro-AmpRT WNV assay. Of field-collected pools that were WNV positive by real-time RT-PCR, 74.5% (70 of 94) were also positive by the Pro-AmpRT WNV assay, resulting in an overall Cohen's kappa agreement of 79.4% between the 2 tests. The Pro-AmpRT WNV assay shows promise as a suitable virus screening tool for vector surveillance programs provided agencies are aware of its characteristics and limitations. |
Laboratory evaluation of the rapid analyte measurement platform assay to detect dengue virus in mosquito pools
Burkhalter KL , Savage HM . J Am Mosq Control Assoc 2021 37 (3) 152-156 We report the results of a laboratory sensitivity and specificity evaluation of the Rapid Analyte Measurement Platform (RAMP®) Dengue Virus (DENV) antigen detection assay, which is designed to detect all serotypes of DENV in mosquito pools. The RAMP DENV assay was able to detect geographically distinct strains of all 4 DENV serotypes in virus-spiked mosquito pools that contained at least 4.3 log10 plaque forming units/ml, although discrete sensitivity limits varied slightly for each serotype. The RAMP DENV assay also detected DENV 1-4 in mosquito pools containing a single infected mosquito and 24 laboratory-reared uninfected mosquitoes. No false positives were detected in negative control mosquito pools or in samples containing high titers of nontarget arboviruses. We found that while the kit-supplied RAMP buffer reduced the infectious titer of DENV, it did not completely inactivate all serotypes. We recommend adding a detergent, Triton X-100, to the buffer to ensure complete inactivation of DENV if the assay is to be conducted at a lower biosafety level than required for DENV handling. |
Experimental Infection of Amblyomma americanum (Acari: Ixodidae) With Bourbon Virus (Orthomyxoviridae: Thogotovirus)
Godsey MS , Rose D , Burkhalter KL , Breuner N , Bosco-Lauth AM , Kosoy OI , Savage HM . J Med Entomol 2021 58 (2) 873-879 Following the recent discovery of Bourbon virus (BRBV) as a human pathogen, and the isolation of the virus from Amblyomma americanum (L.) collected near the location of a fatal human case, we undertook a series of experiments to assess the laboratory vector competence of this tick species for BRBV. Larval ticks were infected using an immersion technique, and transstadial transmission of virus to the nymphal and then to the adult stages was demonstrated. Transstadially infected nymphs transmitted virus to adult ticks at very high rates during cofeeding, indicating the presence of infectious virus in the saliva of engorging ticks. Vertical transmission by transstadially infected females to their progeny occurred, but at a low rate. Rabbits fed on by infected ticks of all active life stages developed high titers of antibody to the virus, demonstrating host exposure to BRBV antigens/live virus during tick blood feeding. These results demonstrate that A. americanum is a competent vector of BRBV and indicate that cofeeding could be critical for enzootic maintenance. |
Declining chlamydia and gonorrhea diagnoses among pregnant women in South Carolina, 2008-2018
Lazenby GB , Savage AH , Horner G , Richmond J , Peterman TA . Sex Transm Dis 2020 48 (3) 141-144 BACKGROUND: Reported U.S. cases of chlamydia and gonorrhea have increased since 2000, while studies in select populations suggest the prevalence of these diseases has decreased. We sought to determine if these diagnoses are increasing among pregnant women delivering at our center. METHODS: This is a retrospective study of women delivering at least one infant > 18 weeks gestation at the Medical University of South Carolina over eleven years (2008-2018). Using the perinatal information system, we collected maternal race, age, insurer, and chlamydia and gonorrhea screening results during the pregnancy of record. Cochran-Armitage trend analyses were performed to evaluate trends in these diagnoses by delivery year for all women and for age/race subgroups. RESULTS: During the study period, there were 24,807 deliveries. The median age of women was 28 years (IQR 23-32). Five percent (5.0%) of women were diagnosed with chlamydia and 1.2% with gonorrhea. The percent of women diagnosed decreased for both chlamydia (9.6% to 3.4%) and gonorrhea (2.5% to 1.1%) (p <0.001 trend analyses for both). A higher percentage of Black women had chlamydia and gonorrhea and both diagnoses declined over time, chlamydia 17.4% to 6.9%, p<0.0001 and gonorrhea 5.8% to 2.1%, p< 0.0001. In a sub-analysis of race and age, Black women < 25 experienced the most significant decline in chlamydia diagnoses (p<0.0001). CONCLUSIONS: We observed declining diagnoses of chlamydia and gonorrhea among pregnant women in our center. Although Black women delivering were more likely to have either diagnoses, they experienced a significant decline in both chlamydia and gonorrhea over time. |
Movement of St. Louis encephalitis virus in the Western United States, 2014- 2018.
Swetnam DM , Stuart JB , Young K , Maharaj PD , Fang Y , Garcia S , Barker CM , Smith K , Godsey MS , Savage HM , Barton V , Bolling BG , Duggal N , Brault AC , Coffey LL . PLoS Negl Trop Dis 2020 14 (6) e0008343 St. Louis encephalitis virus (SLEV) is a flavivirus that circulates in an enzootic cycle between birds and mosquitoes and can also infect humans to cause febrile disease and sometimes encephalitis. Although SLEV is endemic to the United States, no activity was detected in California during the years 2004 through 2014, despite continuous surveillance in mosquitoes and sentinel chickens. In 2015, SLEV-positive mosquito pools were detected in Maricopa County, Arizona, concurrent with an outbreak of human SLEV disease. SLEV-positive mosquito pools were also detected in southeastern California and Nevada in summer 2015. From 2016 to 2018, SLEV was detected in mosquito pools throughout southern and central California, Oregon, Idaho, and Texas. To understand genetic relatedness and geographic dispersal of SLEV in the western United States since 2015, we sequenced four historical genomes (3 from California and 1 from Louisiana) and 26 contemporary SLEV genomes from mosquito pools from locations across the western US. Bayesian phylogeographic approaches were then applied to map the recent spread of SLEV. Three routes of SLEV dispersal in the western United States were identified: Arizona to southern California, Arizona to Central California, and Arizona to all locations east of the Sierra Nevada mountains. Given the topography of the Western United States, these routes may have been limited by mountain ranges that influence the movement of avian reservoirs and mosquito vectors, which probably represents the primary mechanism of SLEV dispersal. Our analysis detected repeated SLEV introductions from Arizona into southern California and limited evidence of year-to-year persistence of genomes of the same ancestry. By contrast, genetic tracing suggests that all SLEV activity since 2015 in central California is the result of a single persistent SLEV introduction. The identification of natural barriers that influence SLEV dispersal enhances our understanding of arbovirus ecology in the western United States and may also support regional public health agencies in implementing more targeted vector mitigation efforts to protect their communities more effectively. |
Consensus and uncertainty in the geographic range of Aedes aegypti and Aedes albopictus in the contiguous United States: Multi-model assessment and synthesis
Monaghan AJ , Eisen RJ , Eisen L , McAllister J , Savage HM , Mutebi JP , Johansson MA . PLoS Comput Biol 2019 15 (10) e1007369 Aedes (Stegomyia) aegypti (L.) and Ae. (Stegomyia) albopictus (Skuse) mosquitoes can transmit dengue, chikungunya, yellow fever, and Zika viruses. Limited surveillance has led to uncertainty regarding the geographic ranges of these vectors globally, and particularly in regions at the present-day margins of habitat suitability such as the contiguous United States. Empirical habitat suitability models based on environmental conditions can augment surveillance gaps to describe the estimated potential species ranges, but model accuracy is unclear. We identified previously published regional and global habitat suitability models for Ae. aegypti (n = 6) and Ae. albopictus (n = 8) for which adequate information was available to reproduce the models for the contiguous U.S. Using a training subset of recently updated county-level surveillance records of Ae. aegypti and Ae. albopictus and records of counties conducting surveillance, we constructed accuracy-weighted, probabilistic ensemble models from these base models. To assess accuracy and uncertainty we compared individual and ensemble model predictions of species presence or absence to both training and testing data. The ensemble models were among the most accurate and also provided calibrated probabilities of presence for each species. The quantitative probabilistic framework enabled identification of areas with high uncertainty and model bias across the U.S. where improved models or additional data could be most beneficial. The results may be of immediate utility for counties considering surveillance and control programs for Ae. aegypti and Ae. albopictus. Moreover, the assessment framework can drive future efforts to provide validated quantitative estimates to support these programs at local, national, and international scales. |
Bloodmeal, Host Selection, and Genetic Admixture Analyses of Culex pipiens Complex (Diptera: Culicidae) Mosquitoes in Chicago, IL.
Kothera L , Mutebi JP , Kenney JL , Saxton-Shaw K , Ward MP , Savage HM . J Med Entomol 2019 57 (1) 78-87 The area in and around Chicago, IL, is a hotspot of West Nile virus activity. The discovery of a Culex pipiens form molestus Forskl population in Chicago in 2009 added to speculation that offspring from hybridization between Cx. pipiens f. pipiens L. and f. molestus could show a preference for feeding on humans. We collected blood-fed female mosquitoes (N = 1,023) from eight residential sites and one public park site in Chicago in July and August 2012. Bloodmeal analysis using the COI (cytochrome c oxidase subunit I) gene was performed to ascertain host choice. Almost all (99%) bloodmeals came from birds, with American Robins (Turdus migratorius L.) and House Sparrows (Passer domesticus L.) making up the largest percentage (74% combined). A forage ratio analysis comparing bird species fed upon and available bird species based on point count surveys indicated Northern Cardinals (Cardinalis cardinalis) and American Robins (Turdus migratorius) appeared to be over-utilized, whereas several species were under-utilized. Two human bloodmeals came from Culex pipiens complex mosquitoes. Admixture and population genetic analyses were conducted with 15 microsatellite loci on head and thorax DNA from the collected blood-fed mosquitoes. A modest amount of hybridization was detected between Cx. pipiens f. pipiens and f. molestus, as well as between f. pipiens and Cx. quinquefasciatus Say. Several pure Cx. quinquefasciatus individuals were noted at the two Trumbull Park sites. Our data suggest that Cx. pipiens complex mosquitoes in the Chicago area are not highly introgressed with f. molestus and appear to utilize avian hosts. |
Using targeted next-generation sequencing to characterize genetic differences associated with insecticide resistance in Culex quinquefasciatus populations from the southern U.S.
Kothera L , Phan J , Ghallab E , Delorey M , Clark R , Savage HM . PLoS One 2019 14 (7) e0218397 Resistance to insecticides can hamper the control of mosquitoes such as Culex quinquefasciatus, known to vector arboviruses such as West Nile virus and others. The strong selective pressure exerted on a mosquito population by the use of insecticides can result in heritable genetic changes associated with resistance. We sought to characterize genetic differences between insecticide resistant and susceptible Culex quinquefasciatus mosquitoes using targeted DNA sequencing. To that end, we developed a panel of 122 genes known or hypothesized to be involved in insecticide resistance, and used an Ion Torrent PGM sequencer to sequence 125 unrelated individuals from seven populations in the southern U.S. whose resistance phenotypes to permethrin and malathion were known from previous CDC bottle bioassay testing. Data analysis consisted of discovering SNPs (Single Nucleotide Polymorphism) and genes with evidence of copy number variants (CNVs) statistically associated with resistance. Ten of the seventeen genes found to be present in higher copy numbers were experimentally validated with real-time PCR. Of those, six, including the gene with the knock-down resistance (kdr) mutation, showed evidence of a >/= 1.5 fold increase compared to control DNA. The SNP analysis revealed 228 unique SNPs that had significant p-values for both a Fisher's Exact Test and the Cochran-Armitage Test for Trend. We calculated the population frequency for each of the 64 nonsynonymous SNPs in this group. Several genes not previously well characterized represent potential candidates for diagnostic assays when further validation is conducted. |
A survey of the mosquitoes of kosrae state, federated states of MICRONESIA, 2016
Rose DA , Godsey MS , Faraji A , Ostrum EM , Savage HM . J Am Mosq Control Assoc 2018 34 (2) 143-146 In response to an outbreak of Zika virus that started in February 2016 on Kosrae Island, Kosrae State, Federated States of Micronesia, we conducted entomological investigations, including a survey to characterize the mosquito fauna on Kosrae, from November 29 to December 8, 2016. Mosquitoes were collected using several surveillance methods in order to sample all stages of the mosquito life cycle. Eggs were collected using ovicups, larvae and pupae were sampled using standard dippers, and adults were collected using aspirators and Biogents-2 Sentinel traps. All species previously recorded from Kosrae State were found in the current survey, confirming their continued presence on the island. Aedes aegypti was detected on Lelu Island, representing a new municipal record. The collection of Ae. vexans nocturnus represents a new species record for Kosrae, increasing the number of known taxa on this island from 6 to 7. The report herein provides updated knowledge of the mosquitoes that occur on Kosrae State, Federated States of Micronesia. |
Notes from the field: Spatially associated coincident and noncoincident cases of La Crosse encephalitis - North Carolina, 2002-2017
Byrd BD , Williams CJ , Staples JE , Burkhalter KL , Savage HM , Doyle MS . MMWR Morb Mortal Wkly Rep 2018 67 (39) 1104-1105 La Crosse virus (LACV) is the most common cause of pediatric arthropod-borne viral (arboviral) encephalitis in the United States (1). It is a California serogroup bunyavirus primarily transmitted by the eastern tree-hole mosquito (Aedes triseriatus) (2). LACV encephalitis is a reportable condition in North Carolina and is a nationally notifiable disease. In North Carolina, LACV encephalitis is the most common endemic arboviral disease reported in humans, with seven western counties accounting for approximately 80% of confirmed cases since 2003 (3). The fatality rate for LACV encephalitis is <1%, with most patients recovering without overt clinical sequelae; however, long-term neurologic sequelae reported in some patients include recurrent seizures, hemiparesis, and cognitive and neurobehavioral abnormalities (4). |
Heartland virus epidemiology, vector association, and disease potential
Brault AC , Savage HM , Duggal NK , Eisen RJ , Staples JE . Viruses 2018 10 (9) First identified in two Missouri farmers exhibiting low white-blood-cell and platelet counts in 2009, Heartland virus (HRTV) is genetically closely related to severe fever with thrombocytopenia syndrome virus (SFTSV), a tick-borne phlebovirus producing similar symptoms in China, Korea, and Japan. Field isolations of HRTV from several life stages of unfed, host-seeking Amblyomma americanum, the lone star tick, implicated it as a putative vector capable of transstadial transmission. Laboratory vector competence assessments confirmed transstadial transmission of HRTV, demonstrated vertical infection, and showed co-feeding infection between A. americanum. A vertical infection rate of 33% from adult females to larvae in the laboratory was observed, while only one of 386 pools of molted nymphs (1930) reared from co-feeding larvae was positive for HRTV (maximum-likelihood estimate of infection rate = 0.52/1000). Over 35 human HRTV cases, all within the distribution range of A. americanum, have been documented. Serological testing of wildlife in areas near the index human cases, as well as in widely separated regions of the eastern United States where A. americanum occur, indicated many potential hosts such as raccoons and white-tailed deer. Attempts, however, to experimentally infect mice, rabbits, hamsters, chickens, raccoons, goats, and deer failed to produce detectable viremia. Immune-compromised mice and hamsters are the only susceptible models. Vertical infection augmented by co-feeding transmission could play a role in maintaining the virus in nature. A more complete assessment of the natural transmission cycle of HRTV coupled with serosurveys and enhanced HRTV disease surveillance are needed to better understand transmission dynamics and human health risks. |
Susceptibility and vectorial capacity of American Aedes albopictus and Aedes aegypti (Diptera: Culicidae) to American Zika virus strains
Lozano-Fuentes S , Kenney JL , Varnado W , Byrd BD , Burkhalter KL , Savage HM . J Med Entomol 2018 56 (1) 233-240 The rapid expansion of Zika virus (ZIKV), following the recent outbreaks of Chikungunya virus, overwhelmed the public health infrastructure in many countries and alarmed many in the scientific community. Aedes aegypti (L.) (Diptera: Culicidae) and Aedes albopictus (Skuse) (Diptera: Culicidae) have previously been incriminated as the vectors of these pathogens in addition to dengue virus. In our study, we challenged low generation Ae. aegypti (Chiapas, Mexico) and Ae. albopictus (North Carolina, Mississippi), with three strains of ZIKV, Puerto Rico (GenBank: KU501215), Honduras (GenBank: KX694534), and Miami (GenBank: MF988743). Following an oral challenge with 107.5 PFU/ml of the Puerto Rico strain, we observed high infection and dissemination rates in both species (95%). We report estimated transmission rates for both species (74 and 33%, for Ae. aegypti (L.) (Diptera: Culicidae) and Ae. albopictus (Skuse) (Diptera: Culicidae), respectively), and the presence of a probable salivary gland barrier in Ae. albopictus to Zika virus. Finally, we calculated vectorial capacity for both species and found that Ae. albopictus had a slightly lower vectorial capacity when compared with Ae. aegypti.Second Language La rapida expansion del virus Zika, poco despues de las epidemias de chikungunya, rebaso la infraestructura de salud publica en muchos paises y sorprendio a muchos en la comunidad cientifica. Notablemente, Aedes aegypti y Aedes albopictus transmiten estos patogenos ademas del virus del dengue. En este estudio se expusieron con tres cepas americanas de virus Zika a grupos de Aedes aegypti y Aedes albopictus de generacion reciente. Encontramos altos porcentajes de infeccion y diseminacion en ambas especies (95%). Se reporta, la transmision viral en ambas especies (74 y 33%, para Aedes aegypti and Aedes albopictus, respectivamente) y una probable barrera a nivel de glandulas salivarias. Finalmente, calculamos la capacidad vectorial para ambas especies. |
Surveillance for Heartland and Bourbon viruses in Eastern Kansas, June 2016
Savage HM , Godsey MS Jr , Tatman J , Burkhalter KL , Hamm A , Panella NA , Ghosh A , Raghavan RK . J Med Entomol 2018 55 (6) 1613-1616 In June 2016, we continued surveillance for tick-borne viruses in eastern Kansas following upon a larger surveillance program initiated in 2015 in response to a fatal human case of Bourbon virus (BRBV) (Family Orthomyxoviridae: Genus Thogotovirus). In 4 d, we collected 14,193 ticks representing four species from four sites. Amblyomma americanum (L.) (Acari: Ixodidae) accounted for nearly all ticks collected (n = 14,116, 99.5%), and the only other species identified were Amblyomma maculatum Koch (Acari: Ixodidae), Dermacentor variabilis (Say) (Acari: Ixodidae) and Ixodes scapularis Say (Acari: Ixodidae). All ticks were tested for both BRBV and Heartland virus (Family Bunyaviridae: Genus Phlebovirus) in 964 pools. Five Heartland virus positive tick pools were detected and confirmed by real-time reverse transcription PCR (rRT-PCR), while all pools tested negative for BRBV. Each Heartland positive pool was composed of 25 A. americanum nymphs with positive pools collected at three different sites in Bourbon County. A. americanum is believed to be the primary vector of both Heartland and BRBVs to humans based upon multiple detections of virus in field-collected ticks, its abundance, and its aggressive feeding behavior on mammals including humans. However, it is possible that A. americanum encounters viremic vertebrate hosts of BRBV less frequently than viremic hosts of Heartland virus, or that BRBV is less efficiently passed among ticks by co-feeding, or less efficiently passed vertically from infected female ticks to their offspring resulting in lower field infection rates. |
Ceragenins are active against drug-resistant Candida auris clinical isolates in planktonic and biofilm forms
Hashemi MM , Rovig J , Holden BS , Taylor MF , Weber S , Wilson J , Hilton B , Zaugg AL , Ellis SW , Yost CD , Finnegan PM , Kistler CK , Berkow EL , Deng S , Lockhart SR , Peterson M , Savage PB . J Antimicrob Chemother 2018 73 (6) 1537-1545 Background: Candida auris has emerged as a serious threat to human health. Of particular concern are the resistance profiles of many clinical isolates, with some being resistant to multiple classes of antifungals. Objectives: Measure susceptibilities of C. auris isolates, in planktonic and biofilm forms, to ceragenins (CSAs). Determine the effectiveness of selected ceragenins in gel and cream formulations in eradicating fungal infections in tissue explants. Materials and methods: A collection of 100 C. auris isolates available at CDC was screened for susceptibility to a lead ceragenin. A smaller collection was used to characterize antifungal activities of other ceragenins against organisms in planktonic and biofilm forms. Effects of ceragenins on fungal cells and biofilms were observed via microscopy. An ex vivo model of mucosal fungal infection was used to evaluate formulated forms of lead ceragenins. Results: Lead ceragenins displayed activities comparable to those of known antifungal agents against C. auris isolates with MICs of 0.5-8 mg/L and minimum fungicidal concentrations (MFCs) of 2-64 mg/L. No cross-resistance with other antifungals was observed. Fungal cell morphology was altered in response to ceragenin treatment. Ceragenins exhibited activity against sessile organisms in biofilms. Gel and cream formulations including 2% CSA-44 or CSA-131 resulted in reductions of over 4 logs against established fungal infections in ex vivo mucosal tissues. Conclusions: Ceragenins demonstrated activity against C. auris, suggesting that these compounds warrant further study to determine whether they can be used for topical applications to skin and mucosal tissues for treatment of infections with C. auris and other fungi. |
Digitizing medicines for remote capture of oral medication adherence using co-encapsulation
Browne SH , Peloquin C , Santillo F , Haubrich R , Muttera L , Moser K , Savage GM , Benson CA , Blaschke TF . Clin Pharmacol Ther 2018 103 (3) 502-510 High-resolution measurement of medication adherence is essential to personalized drug therapy. A US Food and Drug Administration (FDA)-cleared device, using an edible ingestion sensor (IS), external wearable patch, and paired mobile device can detect and record ingestion events. Oral medications must be combined with an IS to generate precise "digitized-medication" ingestion records. We developed a Good Manufacturing Practice protocol to repackage oral medications with the IS within certified Capsugel capsules, termed co-encapsulation (CoE). A randomized bioequivalence study of CoE-IS-Rifamate (Isoniazid/Rifampin 150/300 mg) vs. native-Rifamate was conducted in 12 patients with active Mycobacterium tuberculosis and demonstrated bioequivalence using the population method ratio test (95% confidence interval). Subsequently, CoE-IS-medications across all biopharmaceutical classes underwent in vitro dissolution testing utilizing USP and FDA guidelines. CoE-IS medications tested met USP dissolution specifications and were equivalent to their native formulations. CoE combines oral medications with the IS without altering the quality of the native formulation, generating "digitized" medications for remote capture of dosing histories. |
Surveillance for tick-borne viruses near the location of a fatal human case of Bourbon virus (Family Orthomyxoviridae: Genus Thogotovirus) in Eastern Kansas, 2015
Savage HM , Godsey MS Jr , Panella NA , Burkhalter KL , Manford J , Trevino-Garrison IC , Straily A , Wilson S , Bowen J , Raghavan RK . J Med Entomol 2018 55 (3) 701-705 Bourbon virus (Family Orthomyxoviridae: Genus Thogotovirus) was first isolated from a human case-patient residing in Bourbon County, Kansas, who subsequently died. Before becoming ill in late spring of 2014, the patient reported several tick bites. In response, we initiated tick surveillance in Bourbon County and adjacent southern Linn County during spring and summer of 2015. We collected 20,639 host-seeking ticks representing four species from 12 sites. Amblyomma americanum (L.) (Acari: Ixodidae) and Dermacentor variabilis (Say) (Acari: Ixodidae) accounted for nearly all ticks collected (99.99%). Three tick pools, all composed of adult A. americanum ticks collected in Bourbon County, were virus positive. Two pools were Heartland virus (Family Bunyaviridae: Genus Phlebovirus) positive, and one was Bourbon virus positive. The Bourbon virus positive tick pool was composed of five adult females collected on a private recreational property on June 5. Detection of Bourbon virus in the abundant and aggressive human-biting tick A. americanum in Bourbon County supports the contention that A. americanum is a vector of Bourbon virus to humans. The current data combined with virus detections in Missouri suggest that Bourbon virus is transmitted to humans by A. americanum ticks, including both the nymphal and adult stages, that ticks of this species become infected as either larvae, nymphs or both, perhaps by feeding on viremic vertebrate hosts, by cofeeding with infected ticks, or both, and that Bourbon virus is transstadially transmitted. Multiple detections of Heartland virus and Bourbon virus in A. americanum ticks suggest that these viruses share important components of their transmission cycles. |
Shortages of benzathine penicillin for prevention of mother-to-child transmission of syphilis: An evaluation from multi-country surveys and stakeholder interviews
Nurse-Findlay S , Taylor MM , Savage M , Mello MB , Saliyou S , Lavayen M , Seghers F , Campbell ML , Birgirimana F , Ouedraogo L , Newman Owiredu M , Kidula N , Pyne-Mercier L . PLoS Med 2017 14 (12) e1002473 BACKGROUND: Benzathine penicillin G (BPG) is the only recommended treatment to prevent mother-to-child transmission of syphilis. Due to recent reports of country-level shortages of BPG, an evaluation was undertaken to quantify countries that have experienced shortages in the past 2 years and to describe factors contributing to these shortages. METHODS AND FINDINGS: Country-level data about BPG shortages were collected using 3 survey approaches. First, a survey designed by the WHO Department of Reproductive Health and Research was distributed to 41 countries and territories in the Americas and 41 more in Africa. Second, WHO conducted an email survey of 28 US Centers for Disease Control and Prevention country directors. An additional 13 countries were in contact with WHO for related congenital syphilis prevention activities and also reported on BPG shortages. Third, the Clinton Health Access Initiative (CHAI) collected data from 14 countries (where it has active operations) to understand the extent of stock-outs, in-country purchasing, usage behavior, and breadth of available purchasing options to identify stock-outs worldwide. CHAI also conducted in-person interviews in the same 14 countries to understand the extent of stock-outs, in-country purchasing and usage behavior, and available purchasing options. CHAI also completed a desk review of 10 additional high-income countries, which were also included. BPG shortages were attributable to shortfalls in supply, demand, and procurement in the countries assessed. This assessment should not be considered globally representative as countries not surveyed may also have experienced BPG shortages. Country contacts may not have been aware of BPG shortages when surveyed or may have underreported medication substitutions due to desirability bias. Funding for the purchase of BPG by countries was not evaluated. In all, 114 countries and territories were approached to provide information on BPG shortages occurring during 2014-2016. Of unique countries and territories, 95 (83%) responded or had information evaluable from public records. Of these 95 countries and territories, 39 (41%) reported a BPG shortage, and 56 (59%) reported no BPG shortage; 10 (12%) countries with and without BPG shortages reported use of antibiotic alternatives to BPG for treatment of maternal syphilis. Market exits, inflexible production cycles, and minimum order quantities affect BPG supply. On the demand side, inaccurate forecasts and sole sourcing lead to under-procurement. Clinicians may also incorrectly prescribe BPG substitutes due to misperceptions of quality or of the likelihood of adverse outcomes. CONCLUSIONS: Targets for improvement include drug forecasting and procurement, and addressing provider reluctance to use BPG. Opportunities to improve global supply, demand, and use of BPG should be prioritized alongside congenital syphilis elimination efforts. |
Bourbon virus in field-collected ticks, Missouri, USA
Savage HM , Burkhalter KL , Godsey MS Jr , Panella NA , Ashley DC , Nicholson WL , Lambert AJ . Emerg Infect Dis 2017 23 (12) 2017-2022 Bourbon virus (BRBV) was first isolated in 2014 from a resident of Bourbon County, Kansas, USA, who died of the infection. In 2015, an ill Payne County, Oklahoma, resident tested positive for antibodies to BRBV, before fully recovering. We retrospectively tested for BRBV in 39,096 ticks from northwestern Missouri, located 240 km from Bourbon County, Kansas. We detected BRBV in 3 pools of Amblyomma americanum (L.) ticks: 1 pool of male adults and 2 pools of nymphs. Detection of BRBV in A. americanum, a species that is aggressive, feeds on humans, and is abundant in Kansas and Oklahoma, supports the premise that A. americanum is a vector of BRBV to humans. BRBV has not been detected in nonhuman vertebrates, and its natural history remains largely unknown. |
Prenatal and early life triclosan and parabens exposure and allergic outcomes
Lee-Sarwar K , Hauser R , Calafat AM , Ye X , O'Connor GT , Sandel M , Bacharier LB , Zeiger RS , Laranjo N , Gold DR , Weiss ST , Litonjua AA , Savage JH . J Allergy Clin Immunol 2017 142 (1) 269-278 e15 BACKGROUND: In cross-sectional studies, triclosan and parabens, ubiquitous ingredients in personal care and other products, are associated with allergic disease. OBJECTIVES: We investigated the association between prenatal and early life triclosan and parabens exposure and childhood allergic disease in a prospective, longitudinal study. METHODS: Subjects were enrollees in VDAART, the Vitamin D Antenatal Asthma Reduction Trial. Triclosan, methyl paraben and propyl paraben concentrations were quantified in maternal plasma samples pooled from first and third trimesters and urine samples from children at age 3 or 4 years. Outcomes were parental report of physician-diagnosed asthma or recurrent wheezing, and allergic sensitization to food or environmental antigens based on serum specific IgE levels at age 3 in high-risk children. RESULTS: Analysis included 467 mother-child pairs. Overall, there were no statistically significant associations of maternal plasma or child urine triclosan or parabens concentrations with asthma or recurrent wheeze, food or environmental sensitization at age 3. A trend toward an inverse association between triclosan and parabens exposure and allergic sensitization was observed. There was evidence of effect measure modification by sex, with higher odds of environmental sensitization associated with increasing concentrations of parabens in males compared to females. CONCLUSIONS: We did not identify a consistent association between prenatal and early life triclosan or parabens concentrations and childhood asthma, recurrent wheeze or allergic sensitization in the overall study population. The differential effects of triclosan or parabens exposure on allergic sensitization by sex observed in this study warrants further exploration. |
Modeling the environmental suitability for Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus (Diptera: Culicidae) in the contiguous United States
Johnson TL , Haque U , Monaghan AJ , Eisen L , Hahn MB , Hayden MH , Savage HM , McAllister J , Mutebi JP , Eisen RJ . J Med Entomol 2017 54 (6) 1605-1614 The mosquitoes Aedes (Stegomyia) aegypti (L.)(Diptera:Culicidae) and Ae. (Stegomyia) albopictus (Skuse) (Diptera:Culicidae) transmit dengue, chikungunya, and Zika viruses and represent a growing public health threat in parts of the United States where they are established. To complement existing mosquito presence records based on discontinuous, non-systematic surveillance efforts, we developed county-scale environmental suitability maps for both species using maximum entropy modeling to fit climatic variables to county presence records from 1960-2016 in the contiguous United States. The predictive models for Ae. aegypti and Ae. albopictus had an overall accuracy of 0.84 and 0.85, respectively. Cumulative growing degree days (GDDs) during the winter months, an indicator of overall warmth, was the most important predictive variable for both species and was positively associated with environmental suitability. The number (percentage) of counties classified as environmentally suitable, based on models with 90 or 99% sensitivity, ranged from 1,443 (46%) to 2,209 (71%) for Ae. aegypti and from 1,726 (55%) to 2,329 (75%) for Ae. albopictus. Increasing model sensitivity results in more counties classified as suitable, at least for summer survival, from which there are no mosquito records. We anticipate that Ae. aegypti and Ae. albopictus will be found more commonly in counties classified as suitable based on the lower 90% sensitivity threshold compared with the higher 99% threshold. Counties predicted suitable with 90% sensitivity should therefore be a top priority for expanded mosquito surveillance efforts while still keeping in mind that Ae. aegypti and Ae. albopictus may be introduced, via accidental transport of eggs or immatures, and potentially proliferate during the warmest part of the year anywhere within the geographic areas delineated by the 99% sensitivity model. |
Duplex Real-Time PCR Assay Distinguishes Aedes aegypti From Ae. albopictus (Diptera: Culicidae) Using DNA From Sonicated First-Instar Larvae.
Kothera L , Byrd B , Savage HM . J Med Entomol 2017 54 (6) 1567-1572 Aedes aegypti (L.) and Ae. albopictus (Skuse) are important arbovirus vectors in the United States, and the recent emergence of Zika virus disease as a public health concern in the Americas has reinforced a need for tools to rapidly distinguish between these species in collections made by vector control agencies. We developed a duplex real-time PCR assay that detects both species and does not cross-amplify in any of the other seven Aedes species tested. The lower limit of detection for our assay is equivalent to approximately 0.03 of a first-instar larva in a 60-microl sample (0.016 ng of DNA per real-time PCR reaction). The assay was sensitive and specific in mixtures of both species that reflected up to a 2,000-fold difference in DNA concentration. In addition, we developed a simple protocol to extract DNA from sonicated first-instar larvae, and used that DNA to test the assay. Because it uses real-time PCR, the assay saves time by not requiring a separate visualization step. This assay can reduce the time needed for vector control agencies to make species identifications, and thus inform decisions about surveillance and control. |
Updated reported distribution of Aedes (Stegomyia) aegypti and Aedes (Stegomyia) albopictus (Diptera: Culicidae) in the United States, 1995-2016
Hahn MB , Eisen L , McAllister J , Savage HM , Mutebi JP , Eisen RJ . J Med Entomol 2017 54 (5) 1420-1424 Aedes (Stegomyia) aegypti (L.) and Aedes (Stegomyia) albopictus (Skuse) are potential vectors of Zika, dengue, and chikungunya viruses in the United States. A Zika virus outbreak in Florida in the summer of 2016, driven by Ae. aegypti and resulting in > 200 locally acquired cases of human illness, underscored the need for up-to-date information on the geographic distribution of Ae. aegypti and Ae. albopictus in the United States. In early 2016, we conducted a survey and literature review to compile county records for presence of Ae. aegypti and Ae. albopictus in the United States from 1995 to 2016. Surveillance for these vectors was intensified across the United States during the summer and fall of 2016. At the end of 2016, we therefore conducted a follow-up survey of mosquito control agencies, university researchers, and state and local health departments to document new collection records for Ae. aegypti and Ae. albopictus. The repeated survey at the end of the year added Ae. aegypti collection records from 38 new counties and Ae. albopictus collection records from 127 new counties, representing a 21 and 10 percent increase, respectively, in the number of counties with reported presence of these mosquitoes compared with the previous report. Moreover, through our updated survey, 40 and 183 counties, respectively, added additional years of collection records for Ae. aegypti and Ae. albopictus from 1995 to 2016. Our findings underscore the continued need for systematic surveillance of Ae. aegypti and Ae. albopictus. |
Zika Virus Infection in Patient with No Known Risk Factors, Utah, USA, 2016
Krow-Lucal ER , Novosad SA , Dunn AC , Brent CR , Savage HM , Faraji A , Peterson D , Dibbs A , Vietor B , Christensen K , Laven JJ , Godsey MS Jr , Christensen B , Beyer B , Cortese MM , Johnson NC , Panella AJ , Biggerstaff BJ , Rubin M , Fridkin SK , Staples JE , Nakashima AK . Emerg Infect Dis 2017 23 (8) 1260-1267 In 2016, Zika virus disease developed in a man (patient A) who had no known risk factors beyond caring for a relative who died of this disease (index patient). We investigated the source of infection for patient A by surveying other family contacts, healthcare personnel, and community members, and testing samples for Zika virus. We identified 19 family contacts who had similar exposures to the index patient; 86 healthcare personnel had contact with the index patient, including 57 (66%) who had contact with body fluids. Of 218 community members interviewed, 28 (13%) reported signs/symptoms and 132 (61%) provided a sample. Except for patient A, no other persons tested had laboratory evidence of recent Zika virus infection. Of 5,875 mosquitoes collected, none were known vectors of Zika virus and all were negative for Zika virus. The mechanism of transmission to patient A remains unknown but was likely person-to-person contact with the index patient. |
Transmission incompetence of Culex quinquefasciatus and Culex pipiens pipiens from North America for Zika virus
Kenney JL , Romo H , Duggal NK , Tzeng WP , Burkhalter KL , Brault AC , Savage HM . Am J Trop Med Hyg 2017 96 (5) 1235-1240 AbstractIn late 2014, Zika virus (ZIKV; Flaviviridae, Flavivirus) emerged as a significant arboviral disease threat in the Western hemisphere. Aedes aegypti and Aedes albopictus have been considered the principal vectors of ZIKV in the New World due to viral isolation frequency and vector competence assessments. Limited reports of Culex transmission potential have highlighted the need for additional vector competence assessments of North American Culex species. Accordingly, North American Culex pipiens and Culex quinquefasciatus were orally exposed and intrathoracically inoculated with the African prototype ZIKV strain and currently circulating Asian lineage ZIKV strains to assess infection, dissemination, and transmission potential. Results indicated that these two North American Culex mosquito species were highly refractory to oral infection with no dissemination or transmission observed with any ZIKV strains assessed. Furthermore, both Culex mosquito species intrathoracically inoculated with either Asian or African lineage ZIKVs failed to expectorate virus in saliva. These in vivo results were further supported by the observation that multiple mosquito cell lines of Culex species origin demonstrated significant growth restriction of ZIKV strains compared with Aedes-derived cell lines. In summation, no evidence for the potential of Cx. pipiens or Cx. quinquefasciatus to serve as a competent vector for ZIKV transmission in North America was observed. |
Detection of Zika Virus in Desiccated Mosquitoes by Real-Time Reverse Transcription PCR and Plaque Assay.
Burkhalter KL , Savage HM . Emerg Infect Dis 2017 23 (4) 680-681 We assayed Zika virus-infected mosquitoes stored at room temperature for <30 days for live virus by using plaque assay and virus RNA by using real-time reverse transcription PCR. Viable virus was detected in samples stored <10 days, and virus RNA was detected in samples held for 30 days. |
Preliminary findings from an investigation of Zika virus infection in a patient with no known risk factors - Utah, 2016
Brent C , Dunn A , Savage H , Faraji A , Rubin M , Risk I , Garcia W , Cortese M , Novosad S , Krow-Lucal ER , Crain J , Hill M , Atkinson A , Peterson D , Christensen K , Dimond M , Staples JE , Nakashima A . MMWR Morb Mortal Wkly Rep 2016 65 (36) 981-982 On July 12, 2016, the Utah Department of Health (UDOH) was notified by a clinician caring for an adult (patient A) who was evaluated for fever, rash, and conjunctivitis that began on July 1. Patient A had not traveled to an area with ongoing Zika virus transmission; had not had sexual contact with a person who recently traveled; and had not received a blood transfusion, organ transplant, or mosquito bites. Patient A provided care over several days to an elderly male family contact (the index patient) who contracted Zika virus abroad. The index patient developed septic shock with multiple organ failure and died in the hospital on June 25, 2016. The index patient's blood specimen obtained 2 days before his death had a level of viremia approximately 100,000 times higher than the average level reported in persons infected with Zika virus. Zika virus infection was diagnosed in patient A by real-time reverse transcription-polymerase chain reaction (rRT-PCR) testing on a urine specimen collected 7 days after symptom onset. In addition, a serum specimen collected 11 days after symptom onset, after patient A's symptoms had resolved, was positive for antibodies to Zika virus by Zika immunoglobulin M (IgM) capture enzyme-linked immunosorbent assay (MAC-ELISA) and had neutralizing antibodies detected by plaque-reduction neutralization testing (PRNT). Working with Salt Lake and Davis County Health Departments, UDOH requested assistance from CDC with an investigation to determine patient A's exposures and determine a probable source of infection. |
Design for mosquito abundance, diversity, and phenology sampling within the National Ecological Observatory Network
Hoekman D , Springer YP , Barker CM , Barrera R , Blackmore MS , Bradshaw WE , Foley DH , Ginsberg HS , Hayden MH , Holzapfel CM , Juliano SA , Kramer LD , LaDeau SL , Livdahl TP , Moore CG , Nasci RS , Reisen WK , Savage HM . Ecosphere 2016 7 (5) e01320 The National Ecological Observatory Network (NEON) intends to monitor mosquito populations across its broad geographical range of sites because of their prevalence in food webs, sensitivity to abiotic factors, and relevance for human health. We describe the design of mosquito population sampling in the context of NEON's long-term continental scale monitoring program, emphasizing the sampling design schedule, priorities, and collection methods. Freely available NEON data and associated field and laboratory samples, will increase our understanding of how mosquito abundance, demography, diversity, and phenology are responding to land use and climate change. |
Transmission of Heartland virus (Bunyaviridae: Phlebovirus) by experimentally infected Amblyomma americanum (Acari: Ixodidae)
Godsey MS Jr , Savage HM , Burkhalter KL , Bosco-Lauth AM , Delorey MJ . J Med Entomol 2016 53 (5) 1226-1233 Heartland virus (HRTV; Bunyaviridae: Phlebovirus) is a recently described cause of human illness in the United States. After field studies conducted in 2012 implicated Amblyomma americanum (L.) as a vector of HRTV, we initiated experiments to assess the vector competence of A. americanum Larval and nymphal ticks were immersed in high-titered suspensions of HRTV, and then tested for virus at various intervals postimmersion. In a later trial larval ticks were immersed in HRTV, followed by engorgement on a rabbit. A subset of postmolt nymphs was tested for HRTV to document transstadial transmission. Putatively infected nymphs were cofed with uninfected colony larvae to assess nonviremic transmission. In another trial, nymphs were fed on a rabbit and allowed to molt to the adult stage. Male and female ticks fed and mated upon a rabbit, and females were allowed to oviposit. Male and spent female ticks were tested for HRTV, and offspring of infected females were tested to assess vertical transmission. Infection rates of ≤50% were observed in immersed larvae and nymphs tested at intervals following immersion. Transstadial transmission from larvae to nymphs and then to adults was documented. HRTV was detected in a pool of nymphs molted from uninfected larvae cofed with infected nymphs. Vertical transmission of HRTV was observed in progeny of infected females. Infected females took longer to oviposit and produced fewer offspring. Serologic conversions (without viremia) in rabbits fed upon by immersed larvae or transstadially infected ticks indicate horizontal transmission of HRTV. |
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