Last data update: Jun 03, 2024. (Total: 46935 publications since 2009)
Records 1-14 (of 14 Records) |
Query Trace: Keckler MS [original query] |
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IMVAMUNE and ACAM2000 provide different protection against disease when administered postexposure in an intranasal monkeypox challenge prairie dog model
Keckler MS , Salzer JS , Patel N , Townsend MB , Nakazawa YJ , Doty JB , Gallardo-Romero NF , Satheshkumar PS , Carroll DS , Karem KL , Damon IK . Vaccines (Basel) 2020 8 (3) The protection provided by smallpox vaccines when used after exposure to Orthopoxviruses is poorly understood. Postexposu re administration of 1st generation smallpox vaccines was effective during eradication. However, historical epidemiological reports and animal studies on postexposure vaccination are difficult to extrapolate to today's populations, and 2nd and 3rd generation vaccines, developed after eradication, have not been widely tested in postexposure vaccination scenarios. In addition to concerns about preparedness for a potential malevolent reintroduction of variola virus, humans are becoming increasingly exposed to naturally occurring zoonotic orthopoxviruses and, following these exposures, disease severity is worse in individuals who never received smallpox vaccination. This study investigated whether postexposure vaccination of prairie dogs with 2nd and 3rd generation smallpox vaccines was protective against monkeypox disease in four exposure scenarios. We infected animals with monkeypox virus at doses of 10(4) pfu (2× LD(50)) or 10(6) pfu (170× LD(50)) and vaccinated the animals with IMVAMUNE(®) or ACAM2000(®) either 1 or 3 days after challenge. Our results indicated that postexposure vaccination protected the animals to some degree from the 2× LD(50), but not the 170× LD(5) challenge. In the 2× LD(50) challenge, we also observed that administration of vaccine at 1 day was more effective than administration at 3 days postexposure for IMVAMUNE(®), but ACAM2000(®) was similarly effective at either postexposure vaccination time-point. The effects of postexposure vaccination and correlations with survival of total and neutralizing antibody responses, protein targets, take formation, weight loss, rash burden, and viral DNA are also presented. |
Analgesia during monkeypox virus experimental challenge studies in prairie dogs (Cynomys ludovicianus)
Hutson CL , Gallardo-Romero N , Carroll DS , Salzer JS , Ayers JD , Doty JB , Hughes CM , Nakazawa Y , Hudson P , Patel N , Keckler MS , Olson VA , Nagy T . J Am Assoc Lab Anim Sci 2019 58 (4) 485-500 Because human patients with monkeypox virus (MPXV) infection report painful symptoms, it is reasonable to assume that animals infected with MPXV experience some degree of pain. Understanding whether and how analgesics affect MPXV disease progression is crucial when planning in vivo challenge experiments. In the current study, we challenged prairie dogs with a low dose (4 x10(3) pfu) of MPXV and treated with meloxicam (NSAID) or buprenorphine (opioid); control animals did not receive analgesia or received analgesia without MPXV challenge. Subsets of animals from each group were serially euthanized during the course of the study. Disease progression and viral kinetics were similar between groups, but MXPVinfected, meloxicam-treated animals showed increasing trends of morbidity and mortality compared with other groups. Differences between no-analgesia MPXV-infected control animals and MPXV-infected animals treated with buprenorphine were minimal. The findings in the current study allow more informed decisions concerning the use of analgesics during experimental MPXV challenge studies, thereby improving animal welfare. In light of these findings, we have modified our pain scale for this animal model to include the use of buprenorphine for pain relief when warranted after MPXV challenge. |
Outbreak investigation of Pseudomonas aeruginosa infections in a neonatal intensive care unit
Weng MK , Brooks RB , Glowicz J , Keckler MS , Christensen BE , Tsai V , Mitchell CS , Wilson LE , Laxton R , Moulton-Meissner H , Fagan R . Am J Infect Control 2019 47 (9) 1148-1150 A Pseudomonas aeruginosa outbreak was investigated in a neonatal intensive care unit that had experienced a prior similar outbreak. The 8 cases identified included 2 deaths. An investigation found the cause of the outbreak: tap water from contaminated hospital plumbing which was used for humidifier reservoirs, neonatal bathing, and nutritional preparation. Our findings reinforce a recent Centers for Medicare & Medicaid Services memo recommending increased attention to water management to improve awareness, identification, mitigation, and prevention of water-associated, health care-associated infections. |
Development and implementation of evidence-based laboratory safety management tools for a public health laboratory
Keckler MS , Anderson K , McAllister S , Rasheed JK , Noble-Wang J . Saf Sci 2019 117 205-216 We developed an evidence-based continuous quality improvement (CQI) cycle for laboratory safety as a method of utilizing survey data to improve safety in a public health laboratory setting. Expert Opinion: The CQI cycle begins with the solicitation of laboratory staff input via an annual survey addressing potential chemical, physical and radiological hazards associated with multiple laboratory activities. The survey collects frequency, severity and exposure data related to these activities in the context of the most pathogenic organisms handled at least weekly. Gap Analysis: Step 2 of the CQI cycle used survey data to identify areas needing improvement. Typically, the traditional two-dimensional risk assessment matrix is used to prioritize mitigations. However, we added an additional dimension - frequency of exposure - to create three-dimensional risk maps to better inform and communicate risk priorities. Mitigation Measures: Step 3 of the CQI cycle was to use these results to develop mitigations. This included evaluating the identified risks to determine what risk control measures (elimination, substitution, engineering, administrative or PPE) were needed. In the 2016 iteration of the CQI cycle described here, all mitigations were based on administrative controls. Evaluation and Feedback: The last step of the CQI cycle was to evaluate the inferred effects of interventions through subsequent surveys, allowing for qualitative assessment of intervention effectiveness while simultaneously restarting the cycle by identifying new hazards.Here we describe the tools used to drive this CQI cycle, including the survey tool, risk analysis method, design of interventions and inference of mitigation effectiveness. |
Invasive nontuberculous mycobacterial infections among cardiothoracic surgical patients exposed to heater-cooler devices
Lyman MM , Grigg C , Kinsey CB , Keckler MS , Moulton-Meissner H , Cooper E , Soe MM , Noble-Wang J , Longenberger A , Walker SR , Miller JR , Perz JF , Perkins KM . Emerg Infect Dis 2017 23 (5) 796-805 Invasive nontuberculous mycobacteria (NTM) infections may result from a previously unrecognized source of transmission, heater-cooler devices (HCDs) used during cardiac surgery. In July 2015, the Pennsylvania Department of Health notified the Centers for Disease Control and Prevention (CDC) about a cluster of NTM infections among cardiothoracic surgical patients at 1 hospital. We conducted a case-control study to identify exposures causing infection, examining 11 case-patients and 48 control-patients. Eight (73%) case-patients had a clinical specimen identified as Mycobacterium avium complex (MAC). HCD exposure was associated with increased odds of invasive NTM infection; laboratory testing identified patient isolates and HCD samples as closely related strains of M. chimaera, a MAC species. This investigation confirmed a large US outbreak of invasive MAC infections in a previously unaffected patient population and suggested transmission occurred by aerosolization from HCDs. Recommendations have been issued for enhanced surveillance to identify potential infections associated with HCDs and measures to mitigate transmission risk. |
Notes from the field: Fungal bloodstream infections associated with a compounded intravenous medication at an outpatient oncology clinic - New York City, 2016
Vasquez AM , Lake J , Ngai S , Halbrook M , Vallabhaneni S , Keckler MS , Moulton-Meissner H , Lockhart SR , Lee CT , Perkins K , Perz JF , Antwi M , Moore MS , Greenko J , Adams E , Haas J , Elkind S , Berman M , Zavasky D , Chiller T , Ackelsberg J . MMWR Morb Mortal Wkly Rep 2016 65 (45) 1274-1275 On May 24, 2016, the New York City Department of Health and Mental Hygiene notified CDC of two cases of Exophiala dermatitidis bloodstream infections among patients with malignancies who had received care from a single physician at an outpatient oncology facility (clinic A). Review of January 1-May 31, 2016 microbiology records identified E. dermatitidis bloodstream infections in two additional patients who also had received care at clinic A. All four patients had implanted vascular access ports and had received intravenous (IV) medications, including a compounded IV flush solution containing saline, heparin, vancomycin, and ceftazidime, compounded and administered at clinic A. |
Increases in NKG2C expression on T cells and higher levels of circulating CD8+ B cells are associated with sterilizing immunity provided by a live attenuated SIV vaccine
Hodara VL , Parodi LM , Keckler MS , Giavedoni LD . AIDS Res Hum Retroviruses 2016 32 1125-1134 Vaccines based on live attenuated viruses are highly effective immunogens in the simian immunodeficiency virus (SIV)/rhesus macaque animal model and offer the possibility of studying correlates of protection against infection with virulent virus. We utilized a tether system for studying, in naive macaques and animals vaccinated with a live-attenuated vaccine, the acute events after challenge with pathogenic SIV. This approach allowed for the frequent sampling of small blood volumes without sedation or restraining of the animals, thus reducing the confounding effect of sampling stress. Before challenge, vaccinated animals presented significantly higher levels of proliferating and activated B cells than naive macaques, which were manifested by high expression of CD8 on B cells. After SIV challenge, the only changes observed in protected vaccinated macaques were significant increases in expression of the NK marker NKG2C on CD4 and CD8 T cells. We also identified that infection of naive macaques with SIV resulted in a transient peak of expression of CD20 on CD8 T cells and a constant rise in the number of B cells expressing CD8. Finally, analysis of a larger cohort of vaccinated animals identified that, even when circulating levels of vaccine virus are below the limit of detection, live attenuated vaccines induce systemic increases of IP-10 and perforin. These studies indicate that components of both the innate and adaptive immune systems of animals inoculated with a live-attenuated SIV vaccine respond to and control infection with virulent virus. Persistence of the vaccine virus in tissues may explain the elevated cytokine and B-cell activation levels. In addition, our report underpins the utility of the tether system for the intensive study of acute immune responses to viral infections. |
Notes from the field: Probable mucormycosis among adult solid organ transplant recipients at an acute care hospital - Pennsylvania, 2014-2015
Novosad SA , Vasquez AM , Nambiar A , Arduino MJ , Christensen E , Moulton-Meissner H , Keckler MS , Miller J , Perz JF , Lockhart SR , Chiller T , Gould C , Sehulster L , Brandt ME , Weber JT , Halpin AL , Mody RK . MMWR Morb Mortal Wkly Rep 2016 65 (18) 481-2 On September 17, 2015, the Pennsylvania Department of Health (PADOH) notified CDC of a cluster of three potentially health care-associated mucormycete infections that occurred among solid organ transplant recipients during a 12-month period at hospital A. On September 18, hospital B reported that it had identified an additional transplant recipient with mucormycosis. Hospitals A and B are part of the same health care system and are connected by a pedestrian bridge. PADOH requested CDC's assistance with an on-site investigation, which started on September 22, to identify possible sources of infection and prevent additional infections. |
Comparison of monkeypox virus clade kinetics and pathology within the prairie dog animal model using a serial sacrifice study design
Hutson CL , Carroll DS , Gallardo-Romero N , Drew C , Zaki SR , Nagy T , Hughes C , Olson VA , Sanders J , Patel N , Smith SK , Keckler MS , Karem K , Damon IK . Biomed Res Int 2015 2015 965710 Monkeypox virus (MPXV) infection of the prairie dog is valuable to studying systemic orthopoxvirus disease. To further characterize differences in MPXV clade pathogenesis, groups of prairie dogs were intranasally infected (8 x 103 p.f.u.) with Congo Basin (CB) or West African (WA) MPXV, and 28 tissues were harvested on days 2, 4, 6, 9, 12, 17, and 24 postinfection. Samples were evaluated for the presence of virus and gross and microscopic lesions. Virus was recovered from nasal mucosa, oropharyngeal lymph nodes, and spleen earlier in CB challenged animals (day 4) than WA challenged animals (day 6). For both groups, primary viremia (indicated by viral DNA) was seen on days 6-9 through day 17. CB MPXV spread more rapidly, accumulated to greater levels, and caused greater morbidity in animals compared to WA MPXV. Histopathology and immunohistochemistry (IHC) findings, however, were similar. Two animals that succumbed to disease demonstrated abundant viral antigen in all organs tested, except for brain. Dual-IHC staining of select liver and spleen sections showed that apoptotic cells (identified by TUNEL) tended to colocalize with poxvirus antigen. Interestingly splenocytes were labelled positive for apoptosis more often than hepatocytes in both MPXV groups. These findings allow for further characterization of differences between MPXV clade pathogenesis, including identifying sites that are important during early viral replication and cellular response to viral infection. |
Identification of Giardia duodenalis and Enterocytozoon bieneusi in an epizoological investigation of a laboratory colony of prairie dogs, Cynomys ludovicianus.
Roellig DM , Salzer JS , Carroll DS , Ritter JM , Drew C , Gallardo-Romero N , Keckler MS , Langham G , Hutson CL , Karem KL , Gillespie TR , Visvesvara GS , Metcalfe MG , Damon IK , Xiao L . Vet Parasitol 2015 210 91-7 Since 2005, black-tailed prairie dogs (Cynomys ludovicianus) have been collected for use as research animals from field sites in Kansas, Colorado, and Texas. In January of 2012, Giardia trophozoites were identified by histology, thin-section electron microscopy, and immunofluorescent staining in the lumen of the small intestine and colon of a prairie dog euthanized because of extreme weight loss. With giardiasis suspected as the cause of weight loss, a survey of Giardia duodenalis in the laboratory colony of prairie dogs was initiated. Direct immunofluorescent testing of feces revealed active shedding of Giardia cysts in 40% (n=60) of animals held in the vivarium. All tested fecal samples (n=29) from animals in another holding facility where the index case originated were PCR positive for G. duodenalis with assemblages A and B identified from sequencing triosephosphate isomerase (tpi), glutamate dehydrogenase (gdh), and beta-giardin (bg) genes. Both assemblages are considered zoonotic, thus the parasites in prairie dogs are potential human pathogens and indicate prairie dogs as a possible wildlife reservoir or the victims of pathogen spill-over. Molecular testing for other protozoan gastrointestinal parasites revealed no Cryptosporidium infections but identified a host-adapted Enterocytozoon bieneusi genotype group. |
Humoral immunity to smallpox vaccines and monkeypox virus challenge; proteomic assessment and clinical correlations
Townsend MB , Keckler MS , Patel N , Davies DH , Felgner P , Damon IK , Karem KL . J Virol 2012 87 (2) 900-11 Despite the eradication of smallpox, Orthopoxviruses (OPV) remain public health concerns. Efforts to develop new therapeutics and vaccines for smallpox continue through their evaluation in animal models despite limited understanding of the specific correlates of protective immunity. Recent monkeypox virus challenge studies have established the Black-Tailed Prairie Dog (Cynomys ludovicianus) as a model of human systemic OPV infections. In this study, we assess the induction of humoral immunity in humans and prairie dogs receiving Dryvax(R), ACAM2000(R), or IMVAMUNE(R) vaccines and characterize the proteomic profile of immune recognition using ELISA, neutralization assays and protein microarrays. We confirm anticipated similarities of antigenic protein targets of smallpox vaccine-induced responses in humans and prairie dogs and identify several differences. Subsequent monkeypox intranasal infection of vaccinated prairie dogs results in a significant boost in humoral immunity characterized by a shift in reactivity of increased intensity to a broader range of OPV proteins. This work provides evidence of similarities between the vaccine response in prairie dogs and humans, which enhance the value of the prairie dog model system as an OPV vaccination model and offers novel findings that form a framework for examining humoral immune response induced by systemic infection of orthopoxviruses. |
Establishment of the black-tailed prairie dog (Cynomys ludovicianus) as a novel animal model for comparing smallpox vaccines administered pre-exposure in both high and low-dose monkeypox challenges
Keckler MS , Carroll DS , Gallardo-Romero NF , Lash RR , Salzer JS , Weiss SL , Patel N , Clemmons CJ , Smith SK , Hutson CL , Karem KL , Damon IK . J Virol 2011 85 (15) 7683-98 The 2003 Monkeypox virus (MPXV) outbreak and subsequent laboratory studies demonstrated that the black-tailed prairie dog was susceptible to MPXV infection and that the ensuing rash illness was similar to human systemic orthopoxvirus (OPXV) infections - including a 7 to 9-day incubation period and likely, in some cases, a respiratory route of infection - which distinguishes this model from others. The need for safe and efficacious vaccines for both endemic and epidemic OPVX disease is important to protect an increasingly OPXV naive population. In this study, we tested current and investigational smallpox vaccines for safety, induction of anti-OPXV antibodies, and protection against mortality and morbidity in two MPXV challenges. None of the smallpox vaccines caused illness in this model and all vaccinated animals showed anti-OPXV antibody responses and neutralizing antibody. We tested vaccine efficacy by challenging the animals with 10(5) or 10(6) pfu Congo Basin MPXV 30 days post vaccination and evaluating morbidity and mortality. Our results demonstrate that vaccination with either Dryvax(R) or Acambis2000(R) protected the animals from death with no rash illness. Vaccination with IMVAMUNE(R) also protected the animals from death, albeit with (modified) rash illness. Based on the results of this study, we believe prairie dogs offer a novel and potentially useful small animal model for the safety and efficacy testing of smallpox vaccines in pre- and post-exposure vaccine testing, which is important for public health planning. |
Adverse events post smallpox-vaccination: insights from tail scarification infection in mice with Vaccinia virus
Mota BE , Gallardo-Romero N , Trindade G , Keckler MS , Karem K , Carroll D , Campos MA , Vieira LQ , da Fonseca FG , Ferreira PC , Bonjardim CA , Damon IK , Kroon EG . PLoS One 2011 6 (4) e18924 Adverse events upon smallpox vaccination with fully-replicative strains of Vaccinia virus (VACV) comprise an array of clinical manifestations that occur primarily in immunocompromised patients leading to significant host morbidity/mortality. The expansion of immune-suppressed populations and the possible release of Variola virus as a bioterrorist act have given rise to concerns over vaccination complications should more widespread vaccination be reinitiated. Our goal was to evaluate the components of the host immune system that are sufficient to prevent morbidity/mortality in a murine model of tail scarification, which mimics immunological and clinical features of smallpox vaccination in humans. Infection of C57BL/6 wild-type mice led to a strictly localized infection, with complete viral clearance by day 28 p.i. On the other hand, infection of T and B-cell deficient mice (Rag1(-/-)) produced a severe disease, with uncontrolled viral replication at the inoculation site and dissemination to internal organs. Infection of B-cell deficient animals (microMT) produced no mortality. However, viral clearance in microMT animals was delayed compared to WT animals, with detectable viral titers in tail and internal organs late in infection. Treatment of Rag1(-/-) with rabbit hyperimmune anti-vaccinia serum had a subtle effect on the morbidity/mortality of this strain, but it was effective in reduce viral titers in ovaries. Finally, NUDE athymic mice showed a similar outcome of infection as Rag1(-/-), and passive transfer of WT T cells to Rag1(-/-) animals proved fully effective in preventing morbidity/mortality. These results strongly suggest that both T and B cells are important in the immune response to primary VACV infection in mice, and that T-cells are required to control the infection at the inoculation site and providing help for B-cells to produce antibodies, which help to prevent viral dissemination. These insights might prove helpful to better identify individuals with higher risk of complications after infection with poxvirus. |
Physiologic reference ranges for captive black-tailed prairie dogs (Cynomys ludovicianus)
Keckler MS , Gallardo-Romero NF , Langham GL , Damon IK , Karem KL , Carroll DS . J Am Assoc Lab Anim Sci 2010 49 (3) 274-281 The black-tailed prairie dog (Cynomys ludovicianus) is a member of the order Rodentia and the family Sciuridae. Ecologically, prairie dogs are a keystone species in prairie ecology. This species is used as an animal model for human gallbladder disease and diseases caused by infection with Clostridium difficile, Yersinia pestis, Francisella tularensis, and most recently, Orthopoxvirus. Despite increasing numbers of prairie dogs used in research and kept as pets, few data are available on their baseline physiology in animal facility housing conditions. To establish baseline physiologic reference ranges, we designed a study using 18 wild-caught black-tailed prairie dogs. Telemetry data were analyzed to establish circadian rhythms for activity and temperature. In addition, hematologic and serum chemistry analyses were performed. Baseline measurements were used to establish the mean for each animal, which then were compiled and analyzed to determine the reference ranges. Here we present physiologic data on serum chemistry and hematology profiles, as well as weight, core body temperature, and daily activity patterns for black-tailed prairie dogs. These results reflect the use of multiple measurements from species- and age-matched prairie dogs and likely will be useful to ecologists, scientists interested in using this animal model in research, and veterinarians caring for pet prairie dogs. |
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