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1.
J Spec Educ Technol ; 39(1): 27-40, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38975255

RESUMEN

Virtual Reality Job Interview Training (VR-JIT) and Virtual Interview Training for Transition Age Youth (VIT-TAY) demonstrated initial effectiveness at increasing employment among transition-age youth with disabilities engaged in pre-employment transition services. We characterized activities and estimated the labor and non-labor costs required to prepare schools to implement VR-JIT or VIT-TAY. Implementation preparation and support teams reported labor hours throughout the implementation preparation process. Implementation preparation labor hours at 43 schools cost approximately $1,427 per school, while non-labor costs were $100 per trainee (student). We estimated the replication of implementation preparation labor activities would cost $1,024 per school (range: $841-$1,208). Most costs were spent in delivery planning and teacher training. Given that implementation preparation costs can be barriers to intervention adoption, our results provide critical information for contemplating future implementation of VR-JIT or VIT-TAY.

2.
Interv Sch Clin ; 59(4): 281-286, 2024 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38884047

RESUMEN

This column shares strategies for implementing a technology-based intervention within secondary special education transition services. Virtual Interview Training for Transition-Age Youth is a web-based job interview training that uses educational content and virtual hiring managers (Rita and Travis) to help teach job interview skills. Eight strategies were assembled by research staff, teachers, and administrators during two research studies conducted across n=47 schools that delivered the program (commonly called "Rita and Travis") to n=561 students in secondary special education transition programs. Eight support strategies for implementing Rita and Travis are described. Strategies include: prepare for implementation, ensure administrative support, prioritize training and support, address logistical challenges, integrate the program into the curriculum, take advantage of the administrative center, individualize student support, and offer virtual delivery. The purpose of this column is to prepare others for successful implementation of Virtual Interview Training for Transition-Age Youth within special education transition programs.

3.
Psychiatr Serv ; 75(3): 228-236, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-37644829

RESUMEN

OBJECTIVE: Employment rates among individuals with serious mental illness may be improved by engagement in the individual placement and support (IPS) model of supported employment. Results from a recent randomized controlled trial (RCT) indicate that virtual reality job interview training (VR-JIT) improves employment rates among individuals with serious mental illness who have been actively engaged in IPS for at least 90 days. This study reports on an initial implementation evaluation of VR-JIT during the RCT in a community mental health agency. METHODS: A sequential, complementary mixed-methods design included use of qualitative data to improve understanding of quantitative findings. Thirteen IPS staff trained to lead VR-JIT implementation completed VR-JIT acceptability, appropriateness, and feasibility surveys. Participants randomly assigned to IPS with VR-JIT completed acceptability (N=42) and usability (N=28) surveys after implementation. The authors also conducted five focus groups with IPS staff (N=11) and VR-JIT recipients (N=13) and semistructured interviews with IPS staff (N=9) and VR-JIT recipients (N=4), followed by an integrated analysis process. RESULTS: Quantitative results suggest that IPS staff found VR-JIT to be highly acceptable, appropriate for integration with IPS, and feasible for delivery. VR-JIT was highly acceptable to recipients. Qualitative results add important context to the quantitative findings, including benefits of VR-JIT for IPS staff as well as adaptations for delivering technology-based interventions to individuals with serious mental illness. CONCLUSIONS: These qualitative and quantitative findings are consistent with each other and were influenced by VR-JIT's adaptability and perceived benefits. Tailoring VR-JIT instruction and delivery to individuals with serious mental illness may help optimize VR-JIT implementation within IPS.


Asunto(s)
Empleos Subvencionados , Realidad Virtual , Humanos , Grupos Focales , Capacitación en Servicio , Ensayos Clínicos Controlados Aleatorios como Asunto , Tecnología , Investigación Cualitativa
4.
Front Psychiatry ; 14: 1235056, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38025460

RESUMEN

Background: Employment is a major contributor to quality of life. However, autistic people are often unemployed and underemployed. One potential barrier to employment is the job interview. However, the availability of psychometrically-evaluated assessments of job interviewing skills is limited for autism services providers and researchers. Objective: We analyzed the psychometric properties of the Mock Interview Rating Scale that was adapted for research with autistic transition-age youth (A-MIRS; a comprehensive assessment of video-recorded job interview role-play scenarios using anchor-based ratings for 14 scripted job scenarios). Methods: Eighty-five transition-age youth with autism completed one of two randomized controlled trials to test the effectiveness of two interventions focused on job interview skills. All participants completed a single job interview role-play at pre-test that was scored by raters using the A-MIRS. We analyzed the structure of the A-MIRS using classical test theory, which involved conducting both exploratory and confirmatory factor analyzes, Rasch model analysis and calibration techniques. We then assessed internal consistency, inter-rater reliability, and test-retest reliability. Pearson correlations were used to assess the A-MIRS' construct, convergent, divergent, criterion, and predictive validities by comparing it to demographic, clinical, cognitive, work history measures, and employment outcomes. Results: Results revealed an 11-item unidimensional construct with strong internal consistency, inter-rater reliability, and test-retest reliability. Construct [pragmatic social skills (r = 0.61, p < 0.001), self-reported interview skills (r = 0.34, p = 0.001)], divergent [e.g., age (r = -0.13, p = 0.26), race (r = 0.02, p = 0.87)], and predictive validities [competitive employment (r = 0.31, p = 0.03)] received initial support via study correlations, while convergent [e.g., intrinsic motivation (r = 0.32, p = 0.007), job interview anxiety (r = -0.19, p = 0.08)] and criterion [e.g., prior employment (r = 0.22, p = 0.046), current employment (r = 0.21, p = 0.054)] validities were limited. Conclusion: The psychometric properties of the 11-item A-MIRS ranged from strong-to-acceptable, indicating it may have utility as a reliable and valid method for assessing the job interview skills of autistic transition-age youth.

5.
Contemp Clin Trials Commun ; 34: 101153, 2023 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-37456506

RESUMEN

Autistic transition-age youth experience high rates of unemployment and underemployment, in part due to the social challenges they may face when having conversations in the workplace. In an effort to help enhance conversational abilities in the workplace, our collaborative team partnered to develop WorkChat: A Virtual Workday. Specifically, our team of scientists, community partners, and diversity and inclusion experts participated in a community-engaged process to develop WorkChat using iterative feedback from autistic transition-age youth and their teachers. With initial development complete, this study reports on the protocol that our collaborative team developed, reviewed, and approved to conduct a randomized controlled trial (RCT) to evaluate the real-world effectiveness and initial implementation process outcomes of WorkChat when integrated into post-secondary pre-employment transition services (Pre-ETS). Our aims are to: 1) evaluate whether services-as-usual in combination with WorkChat, compared to services-as-usual with an attention control, enhances social cognition and work-based social ability (between pre- and post-test); reduces anxiety about work-based social encounters (between pre- and post-test), and increases sustained employment by 9-month follow-up; 2) evaluate whether social cognitive ability and work-based social ability mediate the effect of WorkChat on sustained employment; and 3) conduct a multilevel, mixed-method process evaluation of WorkChat implementation.

6.
Front Psychiatry ; 14: 1150307, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37181877

RESUMEN

Background: Over the past 10 years, job interview training has emerged as an area of study among adults with schizophrenia and other serious mental illnesses who face significant challenges when navigating job interviews. The field of mental health services research has limited access to assessments of job interview skills with rigorously evaluated psychometric properties. Objective: We sought to evaluate the initial psychometric properties of a measure assessing job interview skills via role-play performance. Methods: As part of a randomized controlled trial, 90 adults with schizophrenia or other serious mental illnesses completed a job interview role-play assessment with eight items (and scored using anchors) called the mock interview rating scale (MIRS). A classical test theory analysis was conducted including confirmatory factor analyses, Rasch model analysis and calibration, and differential item functioning; along with inter-rater, internal consistency, and test-retest reliabilities. Pearson correlations were used to evaluate construct, convergent, divergent, criterion, and predictive validity by correlating the MIRS with demographic, clinical, cognitive, work history measures, and employment outcomes. Results: Our analyses resulted in the removal of a single item (sounding honest) and yielded a unidimensional total score measurement with support for its inter-rater reliability, internal consistency, and test-retest reliability. There was initial support for the construct, convergent, criterion, and predictive validities of the MIRS, as it correlated with measures of social competence, neurocognition, valuing job interview training, and employment outcomes. Meanwhile, the lack of correlations with race, physical health, and substance abuse lent support for divergent validity. Conclusion: This study presents initial evidence that the seven-item version of the MIRS has acceptable psychometric properties supporting its use to assess job interview skills reliably and validly among adults with schizophrenia and other serious mental illnesses. Clinical Trial Registration: NCT03049813.

7.
J Offender Rehabil ; 62(2): 81-97, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38529012

RESUMEN

Virtual Reality Job Interview Training (VR-JIT) has increased employment rates for returning citizens when added to a successful prison-based employment readiness program. However, implementation preparation cost-expenses prior to offering VR-JIT to intended recipients-is unknown. We estimated the cost of implementation preparation activities (e.g., organizing workflow) for two prisons to deliver VR-JIT. We conducted a budget impact analysis and enumerated the labor costs incurred during this important stage of implementation. Labor costs were approximately $8,847 per prison. Our sensitivity analysis estimated the labor costs to replicate this effort in a new prison to range from $2,877 to $4,306 per prison. Thus, VR-JIT may be an affordable tool for prison-based employment readiness programs to improve gainful employment.

8.
J Vocat Rehabil ; 58(2): 139-154, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-38881791

RESUMEN

BACKGROUND: Autistic transition-age youth are employed at rates far lower than their non-disabled peers as well as youth with other disabilities. Meanwhile, very few studies have evaluated the implementation of job interviewing practices within pre-employment transition services. OBJECTIVE: We conducted an initial implementation evaluation as part of a Type I hybrid randomized controlled effectiveness-implementation trial where we trained teachers to deliver Virtual Interview Training for Transition-Age Youth (VIT-TAY) within five pre-employment transition services programs. METHODS: We used mixed methods to evaluate leader (n=5), teacher (n=15) and autistic transition age youth (n=48) perceptions of VIT-TAY. We used descriptive statistics and thematic network analysis to evaluate survey data. Mixed methods integration was then performed to make comparisons between quantitative and qualitative results. RESULTS: Quantitative survey data revealed that leaders and teachers found VIT-TAY to be highly acceptable and appropriate for pre-employment transition services; findings which were confirmed via thematic network analysis of qualitative interview data. Autistic students reported via quantitative surveys that VIT-TAY was acceptable and usable, which was confirmed via thematic network analysis of open-ended survey data. CONCLUSIONS: This initial implementation evaluation can be used to inform a larger scale implementation evaluation of VIT-TAY in schools.

9.
Crim Justice Behav ; 50(2): 272-293, 2023 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-38881730

RESUMEN

Returning citizens struggle to obtain employment after release from prison, and navigating job interviews is a critical barrier they encounter. Implementing evidence-based interview training is a major gap in prison-based vocational services. We conducted a randomized controlled trial (RCT) to evaluate the feasibility and initial effectiveness of Virtual Reality Job Interview Training within two prisons. Forty-four male returning citizens were randomized to receive service-as-usual (SAU) with VR-JIT (SAU+VR-JIT, n = 28) or SAU (n = 16). Participants reported VR-JIT was highly acceptable and usable. SAU+VR-JIT, as compared to SAU, had significant improvements (with large effect sizes) in interview skills, interview training motivation, and interview anxiety (all p < .05; ηp2 > .15), and greater employment by 6-month follow-up (OR = 7.4, p = .045). VR-JIT can potentially help fill a major gap in prison-based services. Future research is needed to validate VR-JIT effectiveness and evaluate VR-JIT implementation strategies within prisons.

10.
Psychiatr Serv ; 73(9): 1027-1038, 2022 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-35172592

RESUMEN

OBJECTIVE: Virtual Reality Job Interview Training (VR-JIT) is a computerized interview simulator with efficacy at enhancing interview skills and employment outcomes. A randomized controlled trial assessed VR-JIT effectiveness for participants in individual placement and support (IPS), in which approximately 55% of individuals with serious mental illness obtain employment. METHODS: Ninety participants with serious mental illness were randomly assigned to IPS+VR-JIT (N=54) or IPS as usual (N=36), completing pretest-posttest assessments and an employment evaluation at 9 months. Intent-to-treat chi-square analysis, multivariable logistic regression, Cox proportional hazards models, and mixed-effects linear regressions were conducted. Fifty-one percent were IPS nonresponders (i.e., no employment within the first 90 days of IPS). RESULTS: IPS+VR-JIT participants did not have significantly higher employment rates, compared with IPS-as-usual participants (43% versus 28%). IPS nonresponders (N=46) in the IPS+VR-JIT group had greater odds of obtaining employment (odds ratio [OR]=5.82, p=0.014) and shorter time to employment (hazard ratio=2.70, p=0.044) compared with IPS nonresponders in the IPS-as-usual group. Intent-to-treat mixed-effects linear analyses indicated that IPS+VR-JIT, compared with IPS as usual, significantly improved interview skills (p=0.006), interview confidence (p=0.013), and interview anxiety (p=0.019). CONCLUSIONS: VR-JIT's potential benefits (increased employment in a shorter time) appeared to be specific to IPS nonresponders, whereas employment outcomes for recent IPS enrollees were not affected. VR-JIT could be a valuable resource for employment specialists to support IPS nonresponders, because 47% of participants engaged in mock interview training with their specialist. Future research should focus on evaluating the effectiveness and implementation of VR-JIT among IPS nonresponders.


Asunto(s)
Empleos Subvencionados , Trastornos Mentales , Realidad Virtual , Humanos , Capacitación en Servicio , Trastornos Mentales/terapia , Rehabilitación Vocacional
11.
Cell Metab ; 34(1): 171-183.e6, 2022 01 04.
Artículo en Inglés | MEDLINE | ID: mdl-34986332

RESUMEN

Inexorable increases in insulin resistance, lipolysis, and hepatic glucose production (HGP) are hallmarks of type 2 diabetes. Previously, we showed that peripheral delivery of exogenous fibroblast growth factor 1 (FGF1) has robust anti-diabetic effects mediated by the adipose FGF receptor (FGFR) 1. However, its mechanism of action is not known. Here, we report that FGF1 acutely lowers HGP by suppressing adipose lipolysis. On a molecular level, FGF1 inhibits the cAMP-protein kinase A axis by activating phosphodiesterase 4D (PDE4D), which separates it mechanistically from the inhibitory actions of insulin via PDE3B. We identify Ser44 as an FGF1-induced regulatory phosphorylation site in PDE4D that is modulated by the feed-fast cycle. These findings establish the FGF1/PDE4 pathway as an alternate regulator of the adipose-HGP axis and identify FGF1 as an unrecognized regulator of fatty acid homeostasis.


Asunto(s)
Diabetes Mellitus Tipo 2 , Resistencia a la Insulina , Diabetes Mellitus Tipo 2/tratamiento farmacológico , Diabetes Mellitus Tipo 2/metabolismo , Factor 1 de Crecimiento de Fibroblastos/metabolismo , Humanos , Insulina/metabolismo , Lipólisis/fisiología
12.
Career Dev Transit Except Individ ; 45(4): 213-227, 2022 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-38882261

RESUMEN

In a previous randomized controlled trial (RCT), Virtual Interview Training for Transition Age Youth (VIT-TAY) enhanced employment for autistic youth receiving transition services. For this study, a non-randomized hybrid effectiveness-implementation trial evaluated whether VIT-TAY maintained its core implementation and effectiveness functions when scaled out to students with disabilities in 32 schools. Also, we compared the implementation and effectiveness between VIT-TAY and Virtual Reality Job Interview Training (VR-JIT; developed for adults and previously evaluated in students with disabilities). Core implementation functions did not differ between VIT-TAY and VR-JIT. Greater engagement with either training was significantly associated with employment (both p < 0.05). Overall, VIT-TAY was feasibly implemented with high adherence and may be effective at enhancing employment for students with disabilities. Limitations and implications for research and practice are discussed.

13.
Intellect Dev Disabil ; 59(5): 405-421, 2021 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-34551103

RESUMEN

Vocational outcomes among transition-age youth receiving special education services are critically poor and have only incrementally improved since the implementation of the Workforce Innovation Opportunity Act. Few studies highlight whether interviewing may be critical to obtaining vocational outcomes such as competitive employment or internships. This study evaluated vocational interviewing and outcomes among 656 transition-age youth receiving special education pre-employment transition services from 47 schools. Results suggest 20.8% of these youth were currently employed, and 88.8% of these employed youth interviewed prior to obtaining their job, which is higher than anecdotal evidence suggests and speaks to the importance of job interview skills as an intervention target for special education pre-employment transition services. We discuss the implications and directions for further study.


Asunto(s)
Discapacidad Intelectual , Rehabilitación Vocacional , Adolescente , Educación Especial , Empleo , Humanos , Instituciones Académicas
14.
Autism ; 25(6): 1536-1552, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-33567883

RESUMEN

LAY ABSTRACT: Autistic transition age youth struggle with obtaining employment, and interviewing is a critical barrier to getting a job. We adapted an efficacious virtual reality job interview intervention to meet the needs of autistic transition age youth, called the Virtual Interview Training for Transition Age Youth. This study evaluated whether Virtual Interview Training for Transition Age Youth can be feasibly delivered in high school special education settings and whether Virtual Interview Training for Transition Age Youth improves job interview skills, job interview self-efficacy, job interview anxiety, and access to employment. Forty-eight autistic transition age youth received school-based pre-employment services as usual with Virtual Interview Training for Transition Age Youth, while 23 autistic transition age youth received services as usual only. Local teachers trained and supervised autistic transition age youth using Virtual Interview Training for Transition Age Youth. Participants reported Virtual Interview Training for Transition Age Youth was highly acceptable. Participants receiving services as usual and Virtual Interview Training for Transition Age Youth, compared to participants receiving services as usual only, had better job interview skills and lower job interview anxiety as well as greater access to jobs. Overall, Virtual Interview Training for Transition Age Youth appears to be effective at teaching job interview skills that are associated with accessing competitive jobs. Moreover, youth enjoyed Virtual Interview Training for Transition Age Youth and teachers feasibly implemented the tool within special education pre-employment transition services. Future research needs to better understand how autistic transition age youth from culturally diverse backgrounds and different social, behavioral, or mental health challenges may respond to Virtual Interview Training for Transition Age Youth.


Asunto(s)
Trastorno del Espectro Autista , Trastorno Autístico , Adolescente , Empleo , Estudios de Factibilidad , Humanos , Salud Mental
15.
J Spec Educ Technol ; 36(1): 3-17, 2021 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-38911489

RESUMEN

This study reports the results of a single-arm non-controlled, Type 3 hybrid effectiveness-implementation trial evaluating virtual reality job-interview training (VR-JIT) delivered in five pre-employment transition programs comprising 15 schools, 10 administrators, 23 teachers, and 279 youth ages 16-21 years receiving special education pre-employment transition services. Fidelity, expected implementation feasibility, and teacher and student acceptance of VR-JIT were high. Youth completed virtual interviews over six to eight weeks (M = 10.8, SD = 7.4). At the six-month follow-up, teachers reported that youth using VR-JIT had employment rates higher than current national employment rates for youth with disabilities. A multinomial logistic regression revealed VR-JIT engagement was associated with greater employment rates by six-month follow-up (OR=1.63, p=0.002). This study provides promising evidence that VR-JIT may be feasibly implemented with high fidelity in special education pre-employment transition services and can potentially enhance employment outcomes among transition-age youth receiving special education services.

16.
Sci Rep ; 10(1): 16923, 2020 10 09.
Artículo en Inglés | MEDLINE | ID: mdl-33037311

RESUMEN

Burkholderia pseudomallei (Bpm) is a bacterial pathogen that causes Melioidosis, a disease with up to 40% mortality and an infection relapse of 15-23% despite antibiotic treatment. Ineffective clearance of Bpm by antibiotics is believed to be due to persistence, a hibernation-like survival mechanism modulated, in part, by toxin-antitoxin systems (TAS). Several organisms possess a repertoire of TASs but defining environmental cues eliciting their activity is hindered by laborious in vitro experiments, especially when there are many toxins with redundant function. Here, we identified which of 103 proteins in Bpm that share features found in toxins of the TAS and repurposed transcriptional data to identify which ones play a role in surviving intracellular host defenses. Putative toxins with the strongest transcriptional response were found to have low conservation between Bpm strains, while toxins that were constitutively expressed were highly conserved. Further examination of highly conserved toxins BPSS0899, BPSS1321, and BPSL1494 showed that they were functional, and their mutation led to reduce survival within macrophages and reduced in vivo persistence-associated pathology (abscesses) during treatment, but did not affect macrophages persistence. These findings highlight the utility of a data-driven approach to select putative toxins and suggests a selective role for some TAS in host survival.


Asunto(s)
Burkholderia pseudomallei/metabolismo , Sistemas Toxina-Antitoxina/fisiología , Toxinas Biológicas/metabolismo , Animales , Antibacterianos/farmacología , Proteínas Bacterianas/metabolismo , Burkholderia pseudomallei/efectos de los fármacos , Línea Celular Tumoral , Femenino , Humanos , Melioidosis/tratamiento farmacológico , Melioidosis/metabolismo , Ratones , Ratones Endogámicos BALB C , Sistemas Toxina-Antitoxina/efectos de los fármacos , Células U937
17.
Contemp Clin Trials Commun ; 19: 100604, 2020 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-32671283

RESUMEN

The Michigan Department of Corrections operates the Vocational Villages, which are skilled trades training programs set within prisons that include an immersive educational community using virtual reality, robotics, and other technologies to develop employable trades. An enhancement to the Vocational Villages could be an evidence-based job interview training component. Recently, we conducted a series of randomized controlled trials funded by the National Institute of Mental Health to evaluate the efficacy of virtual reality job interview training (VR-JIT). The results suggested that the use of VR-JIT was associated with improved job interview skills and a greater likelihood of receiving job offers within 6 months. The primary goal of this study is to report on the protocol we developed to evaluate the effectiveness of VR-JIT at improving interview skills, increasing job offers, and reducing recidivism when delivered within two Vocational Villages via a randomized controlled trial and process evaluation. Our aims are to: (1) evaluate whether services-as-usual in combination with VR-JIT, compared to services-as-usual alone, enhances employment outcomes and reduces recidivism among returning citizens enrolled in the Vocational Villages; (2) evaluate mechanisms of employment outcomes and explore mechanisms of recidivism; and (3) conduct a multilevel, mixed-method process evaluation of VR-JIT implementation to assess the adoptability, acceptability, scalability, feasibility, and implementation costs of VR-JIT.

18.
Fac Rev ; 9: 23, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-33659955

RESUMEN

Almost every ecosystem on this planet is teeming with microbial communities made of diverse bacterial species. At a reductionist view, many of these bacteria form pairwise interactions, but, as the field of view expands, the neighboring organisms and the abiotic environment can play a crucial role in shaping the interactions between species. Over the years, a strong foundation of knowledge has been built on isolated pairwise interactions between bacteria, but now the field is advancing toward understanding how cohabitating bacteria and natural surroundings affect these interactions. Use of bottom-up approaches, piecing communities together, and top-down approaches that deconstruct communities are providing insight on how different species interact. In this review, we highlight how studies are incorporating more complex communities, mimicking the natural environment, and recurring findings such as the importance of cooperation for stability in harsh environments and the impact of bacteria-induced environmental pH shifts. Additionally, we will discuss how omics are being used as a top-down approach to identify previously unknown interspecies bacterial interactions and the challenges of these types of studies for microbial ecology.

19.
Cell Microbiol ; 21(12): e13096, 2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31400259

RESUMEN

Burkholderia pseudomallei is the causative agent of melioidosis, a disease with a mortality rate of up to 40% even with treatment. Despite the ability of certain antibiotics to control initial infection, relapse occurs in treated patients. The inability of antibiotics to clear this bacterial infection is in part due to persistence, an evasion mechanism against antibiotics and the effect of host defenses. Evaluation of antibiotic efficacy against B. pseudomallei revealed that up to 48% of in vitro grown populations can survive in a persister state. Toxin-antitoxin (TA) systems have been previously implicated in modulating bacterial persistence. We generated three isogenic TA mutants and found that loss of each toxin gene did not alter antibiotic persistence or macrophage survival. In response to macrophage-induced persistence, all three toxin mutants demonstrated increased intracellular susceptibility to levofloxacin which in part was due to the inability of the mutants to induce persistence after nitric oxide or nutrient starvation. In an inhalational model of murine melioidosis, both ΔBPSS0395 and ΔBPSS1584 strains were attenuated, and treatment with levofloxacin led to significant reduction in lung colonisation and reduced splenic colonisation by ΔBPSS0395. Based on our findings, these toxins deserve additional evaluation as putative therapeutic targets.


Asunto(s)
Burkholderia pseudomallei/metabolismo , Toxinas Biológicas/metabolismo , Animales , Antibacterianos/farmacología , Burkholderia pseudomallei/efectos de los fármacos , Línea Celular , Femenino , Levofloxacino/farmacología , Melioidosis/tratamiento farmacológico , Ratones , Ratones Endogámicos BALB C , Pruebas de Sensibilidad Microbiana/métodos , Células RAW 264.7
20.
mSphere ; 4(1)2019 01 02.
Artículo en Inglés | MEDLINE | ID: mdl-30602524

RESUMEN

Burkholderia pseudomallei is a Gram-negative facultative intracellular bacterium and the causative agent of melioidosis, a severe infectious disease found throughout the tropics. This organism is closely related to Burkholderia mallei, the etiological agent of glanders disease which primarily affects equines. These two pathogenic bacteria are classified as Tier 1 select agents due to their amenability to aerosolization, limited treatment options, and lack of an effective vaccine. We have previously successfully demonstrated the immunogenicity and protective efficacy of a live attenuated vaccine strain, B. malleiΔtonB Δhcp1 (CLH001). Thus, we applied this successful approach to the development of a similar vaccine against melioidosis by constructing the B. pseudomalleiΔtonB Δhcp1 (PBK001) strain. C57BL/6 mice were vaccinated intranasally with the live attenuated PBK001 strain and then challenged with wild-type B. pseudomallei K96243 by the aerosol route. Immunization with strain PBK001 resulted in full protection (100% survival) against acute aerosolized melioidosis with very low bacterial burden as observed in the lungs, livers, and spleens of immunized mice. PBK001 vaccination induced strong production of B. pseudomallei-specific serum IgG antibodies and both Th1 and Th17 CD4+ T cell responses. Further, humoral immunity appeared to be essential for vaccine-induced protection, whereas CD4+ and CD8+ T cells played a less direct immune role. Overall, PBK001 was shown to be an effective attenuated vaccine strain that activates a robust immune response and offers full protection against aerosol infection with B. pseudomalleiIMPORTANCE In recent years, an increasing number of melioidosis cases have been reported in several regions where melioidosis is endemic and in areas where melioidosis had not commonly been diagnosed. Currently, the estimated burden of disease is around 165,000 new cases annually, including 89,000 cases that have fatal outcomes. This life-threatening infectious disease is caused by B. pseudomallei, which is classified as a Tier 1 select agent. Due to the high case fatality rate, intrinsic resistance to multiple antibiotic treatments, susceptibility to infection via the aerosol route, and potential use as a bioweapon, we have developed an effective live attenuated PBK001 vaccine capable of protecting against aerosolized melioidosis.


Asunto(s)
Vacunas Bacterianas/inmunología , Burkholderia pseudomallei/inmunología , Melioidosis/prevención & control , Animales , Anticuerpos Antibacterianos/sangre , Burkholderia pseudomallei/clasificación , Modelos Animales de Enfermedad , Femenino , Melioidosis/inmunología , Ratones Endogámicos C57BL , Vacunas Atenuadas/inmunología
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