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Article: Clinical and Economic Burden of Valley Fever in Arizona: An Incidence-Based Cost-of-Illness Analysis.

Grizzle, Amy J / Wilson, Leslie / Nix, David E / Galgiani, John N

2020 Volume 8, Issue 2, Page(s) ofaa623

Abstract: Background: Coccidioidomycosis, ie, Valley fever, is an important fungal infection in the Southwest, with half to two thirds of all cases occurring in Arizona. This endemic respiratory disease can range from primary uncomplicated pneumonia to ... ...

Abstract	Background: Coccidioidomycosis, ie, Valley fever, is an important fungal infection in the Southwest, with half to two thirds of all cases occurring in Arizona. This endemic respiratory disease can range from primary uncomplicated pneumonia to disseminated infection such as meningitis with chronic pulmonary complications. Valley fever diagnoses have risen over recent years and cause substantial morbidity and economic burden in Arizona. Methods: We estimated the lifetime cost-of-illness associated with all cases of Valley fever diagnosed in 2019 in Arizona. Natural history of the disease was determined from literature and expert opinion and assigned costs from national data sources to determine lifetime direct and indirect costs (work loss). Results: Total lifetime costs of $736 million were estimated for the 10 359 cases of Valley fever diagnosed in Arizona in 2019. Direct costs of $671 million accounted for over 90% of expenditures, with $65 million in indirect costs. Disseminated infection produces the highest economic burden at $1.26 million direct and $137 400 indirect costs per person. The lowest Valley fever lifetime costs were for cases of primary uncomplicated pneumonia with $23 200 in direct costs and $1300 in lost wages. The average lifetime direct costs across all Valley fever manifestations are $64 800 per person diagnosed in Arizona in 2019 and $6300 for indirect costs. Conclusions: Valley fever is responsible for substantial economic burden in Arizona. Our estimates underscore the value of supporting research into developing more rapid diagnostic tests, better therapies, and ultimately a preventative vaccine to address this important public health problem in Arizona.
Language	English
Publishing date	2020-12-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofaa623
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Improving Early Recognition of Coccidioidomycosis in Urgent Care Clinics: Analysis of an Implemented Education Program.

Pu, Jie / Miranda, Valerie / Minior, Devin / Reynolds, Shane / Rayhorn, Benjamin / Ellingson, Katherine D / Galgiani, John N

Open forum infectious diseases

2023 Volume 10, Issue 1, Page(s) ofac654

Abstract: Background: Only 0.2% of coccidioidomycosis (CM) diagnoses were made in patients (pts) with pneumonia (PNA) in urgent care (UC), because they were not being tested for CM. Our objective in this study was to improve CM testing rates.: Methods: This ... ...

Abstract	Background: Only 0.2% of coccidioidomycosis (CM) diagnoses were made in patients (pts) with pneumonia (PNA) in urgent care (UC), because they were not being tested for CM. Our objective in this study was to improve CM testing rates. Methods: This was a time series of clinician practice before and after an intervention that occurred at UC clinics in Phoenix and Tucson Arizona. All patients in UC were >18 years old. We included information about CM in periodic educational activities for clinicians. Coccidioidal serologic testing (CST), CST results, and their relation to Results: Urgent care received 2.1 million visits from 1.5 million patients. The CST orders per 10 Conclusions: Routine quality improvement activities have significantly but only partially improved rates of testing pts with PNA for CM in UC clinics located in a highly endemic area. Innovative strategies may be needed to improve current practice. Also in our region, EN, independent of PNA, is a strong predictor of CM.
Language	English
Publishing date	2023-01-31
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofac654
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Article ; Online: Cross-Sectional Study of Clinical Predictors of Coccidioidomycosis, Arizona, USA.

Ramadan, Ferris A / Ellingson, Katherine D / Canales, Robert A / Bedrick, Edward J / Galgiani, John N / Donovan, Fariba M

Emerging infectious diseases

2022 Volume 28, Issue 6, Page(s) 1091–1100

Abstract: Demographic and clinical indicators have been described to support identification of coccidioidomycosis; however, the interplay of these conditions has not been explored in a clinical setting. In 2019, we enrolled 392 participants in a cross-sectional ... ...

Abstract	Demographic and clinical indicators have been described to support identification of coccidioidomycosis; however, the interplay of these conditions has not been explored in a clinical setting. In 2019, we enrolled 392 participants in a cross-sectional study for suspected coccidioidomycosis in emergency departments and inpatient units in Coccidioides-endemic regions. We aimed to develop a predictive model among participants with suspected coccidioidomycosis. We applied a least absolute shrinkage and selection operator to specific coccidioidomycosis predictors and developed univariable and multivariable logistic regression models. Univariable models identified elevated eosinophil count as a statistically significant predictive feature of coccidioidomycosis in both inpatient and outpatient settings. Our multivariable outpatient model also identified rash (adjusted odds ratio 9.74 [95% CI 1.03-92.24]; p = 0.047) as a predictor. Our results suggest preliminary support for developing a coccidioidomycosis prediction model for use in clinical settings.
MeSH term(s)	Arizona/epidemiology ; Coccidioides ; Coccidioidomycosis/diagnosis ; Coccidioidomycosis/epidemiology ; Cross-Sectional Studies ; Humans
Language	English
Publishing date	2022-05-24
Publishing country	United States
Document type	Journal Article ; Review ; Research Support, U.S. Gov't, P.H.S.
ZDB-ID	1380686-5
ISSN	1080-6059 ; 1080-6040
ISSN (online)	1080-6059
ISSN	1080-6040
DOI	10.3201/eid2806.212311
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Article ; Online: The WOPR family protein Ryp1 is a key regulator of gene expression, development, and virulence in the thermally dimorphic fungal pathogen Coccidioides posadasii.

Mandel, M Alejandra / Beyhan, Sinem / Voorhies, Mark / Shubitz, Lisa F / Galgiani, John N / Orbach, Marc J / Sil, Anita

PLoS pathogens

2022 Volume 18, Issue 4, Page(s) e1009832

Abstract: Coccidioides spp. are mammalian fungal pathogens endemic to the Southwestern US and other desert regions of Mexico, Central and South America, with the bulk of US infections occurring in California and Arizona. In the soil, Coccidioides grows in a hyphal ...

Abstract	Coccidioides spp. are mammalian fungal pathogens endemic to the Southwestern US and other desert regions of Mexico, Central and South America, with the bulk of US infections occurring in California and Arizona. In the soil, Coccidioides grows in a hyphal form that differentiates into 3-5 micron asexual spores (arthroconidia). When arthroconidia are inhaled by mammals they undergo a unique developmental transition from polar hyphal growth to isotropic expansion with multiple rounds of nuclear division, prior to segmentation, forming large spherules filled with endospores. Very little is understood about the molecular basis of spherule formation. Here we characterize the role of the conserved transcription factor Ryp1 in Coccidioides development. We show that Coccidioides Δryp1 mutants have altered colony morphology under hypha-promoting conditions and are unable to form mature spherules under spherule-promoting conditions. We analyze the transcriptional profile of wild-type and Δryp1 mutant cells under hypha- and spherule-promoting conditions, thereby defining a set of hypha- or spherule-enriched transcripts ("morphology-regulated" genes) that are dependent on Ryp1 for their expression. Forty percent of morphology-regulated expression is Ryp1-dependent, indicating that Ryp1 plays a dual role in both hyphal and spherule development. Ryp1-dependent transcripts include key virulence factors such as SOWgp, which encodes the spherule outer wall glycoprotein. Concordant with its role in spherule development, we find that the Δryp1 mutant is completely avirulent in the mouse model of coccidioidomycosis, indicating that Ryp1-dependent pathways are essential for the ability of Coccidioides to cause disease. Vaccination of C57BL/6 mice with live Δryp1 spores does not provide any protection from lethal C. posadasii intranasal infection, consistent with our findings that the Δryp1 mutant fails to make mature spherules and likely does not express key antigens required for effective vaccination. Taken together, this work identifies the first transcription factor that drives mature spherulation and virulence in Coccidioides.
MeSH term(s)	Animals ; Coccidioides/genetics ; Fungal Proteins ; Gene Expression ; Mammals ; Mice ; Mice, Inbred C57BL ; Spores, Fungal/genetics ; Transcription Factors/genetics ; Virulence
Chemical Substances	Fungal Proteins ; Transcription Factors
Language	English
Publishing date	2022-04-06
Publishing country	United States
Document type	Journal Article
ZDB-ID	2205412-1
ISSN	1553-7374 ; 1553-7374
ISSN (online)	1553-7374
ISSN	1553-7374
DOI	10.1371/journal.ppat.1009832
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Article: Contribution of Biologic Response Modifiers to the Risk of Coccidioidomycosis Severity.

Donovan, Fariba M / Ramadan, Ferris A / Lim, James R / Buchfuhrer, Julia E / Khan, Rebia N / DeQuillfeldt, Natalie P / Davis, Natalie M / Kaveti, Ashwini / De Shadarevian, Melanie / Bedrick, Edward J / Galgiani, John N

Open forum infectious diseases

2022 Volume 9, Issue 3, Page(s) ofac032

Abstract: Background: The risk of coccidioidomycosis (CM) as a life-threatening respiratory illness or disseminated CM (DCM) increases as much as 150-fold in immunosuppressed patients. The safety of biologic response modifiers (BRMs) as treatment for patients ... ...

Abstract	Background: The risk of coccidioidomycosis (CM) as a life-threatening respiratory illness or disseminated CM (DCM) increases as much as 150-fold in immunosuppressed patients. The safety of biologic response modifiers (BRMs) as treatment for patients with autoimmune disease (AI) in CM-endemic regions is not well defined. We sought to determine that risk in the Tucson and Phoenix areas. Methods: We conducted a retrospective study reviewing demographics, Arizona residency length, clinical presentations, specific AI diagnoses, CM test results, and BRM treatments in electronic medical records of patients ≥18 years old with Results: We reviewed 944 charts with overlapping Conclusions: AI does not increase the risk of any specific CM clinical presentation, and BRM treatment of most AI patients does not lead to severe CM. However, BRMs significantly increase the risk of DCM, and prospective studies are needed to identify the immunogenetic subset that permits BRM-associated DCM.
Language	English
Publishing date	2022-01-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2757767-3
ISSN	2328-8957
ISSN	2328-8957
DOI	10.1093/ofid/ofac032
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Article ; Online: Vaccines to Prevent Coccidioidomycosis: A Gene-Deletion Mutant of Coccidioides Posadasii as a Viable Candidate for Human Trials.

Galgiani, John N / Shubitz, Lisa F / Orbach, Marc J / Mandel, M Alejandra / Powell, Daniel A / Klein, Bruce S / Robb, Edward J / Ohkura, Mana / Seka, Devin J / Tomasiak, Thomas M / Monath, Thomas P

Journal of fungi (Basel, Switzerland)

2022 Volume 8, Issue 8

Abstract: Coccidioidomycosis is an endemic fungal infection that is reported in up to 20,000 persons per year and has an economic impact close to $1.5 billion. Natural infection virtually always confers protection from future exposure, and this suggests that a ... ...

Abstract	Coccidioidomycosis is an endemic fungal infection that is reported in up to 20,000 persons per year and has an economic impact close to $1.5 billion. Natural infection virtually always confers protection from future exposure, and this suggests that a preventative vaccine strategy is likely to succeed. We here review progress toward that objective. There has been ongoing research to discover a coccidioidal vaccine over the past seven decades, including one phase III clinical trial, but for reasons of either efficacy or feasibility, a safe and effective vaccine has not yet been developed. This review first summarizes the past research to develop a coccidioidal vaccine. It then details the evidence that supports a live, gene-deletion vaccine candidate as suitable for further development as both a veterinary and a human clinical product. Finally, a plausible vaccine development plan is described which would be applicable to this vaccine candidate and also useful to other future candidates. The public health and economic impact of coccidioidomycosis fully justifies a public private partnership for vaccine development, and the development of a vaccine for this orphan disease will likely require some degree of public funding.
Language	English
Publishing date	2022-08-10
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2784229-0
ISSN	2309-608X ; 2309-608X
ISSN (online)	2309-608X
ISSN	2309-608X
DOI	10.3390/jof8080838
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Article ; Online: Natural history of pulmonary coccidioidomycosis: Further examination of the VA-Armed Forces Database.

Shemuel, Joseph / Bays, Derek J / Thompson, George R / Reef, Susan / Snyder, Linda / Freifeld, Alana J / Huppert, Milt / Salkin, David / Wilson, Machelle D / Galgiani, John N

Medical mycology

2022 Volume 60, Issue 10

Abstract: There are still many limitations related to the understanding of the natural history of differing forms of coccidioidomycosis (CM), including characterizing the spectrum of pulmonary disease. The historical Veterans Administration-Armed Forces database, ... ...

Abstract	There are still many limitations related to the understanding of the natural history of differing forms of coccidioidomycosis (CM), including characterizing the spectrum of pulmonary disease. The historical Veterans Administration-Armed Forces database, recorded primarily before the advent of antifungal therapy, presents an opportunity to characterize the natural history of pulmonary CM. We performed a retrospective cohort study of 342 armed forces service members who were diagnosed with pulmonary CM at VA facilities between 1955 to 1958, followed through 1966, who did not receive antifungal therapy. Patients were grouped by predominant pulmonary finding on chest radiographs. The all-cause mortality was low for all patients (4.6%). Cavities had a median size of 3-3.9 cm (IQR: 2-2.9-4-4.9 cm), with heterogeneous wall thickness and no fluid level, while nodules had a median size of 1-1.19 cm (Interquartile range [IQR] 1-1.9-2-2.9 cm) and sharp borders. The majority of cavities were chronic (85.6%), and just under half were found incidentally. Median complement fixation titers in both the nodular and cavitary groups were negative, with higher titers in the cavitary group overall. This retrospective cohort study of non-disseminated coccidioidomycosis, the largest to date, sheds light on the natural history, serologic markers, and radiologic characteristics of this understudied disease. These findings have implications for the evaluation and management of CM.
MeSH term(s)	Animals ; Coccidioidomycosis/diagnosis ; Coccidioidomycosis/epidemiology ; Coccidioidomycosis/veterinary ; Antifungal Agents/therapeutic use ; Retrospective Studies ; Radiography
Chemical Substances	Antifungal Agents
Language	English
Publishing date	2022-09-27
Publishing country	England
Document type	Journal Article
ZDB-ID	1421796-x
ISSN	1460-2709 ; 1369-3786
ISSN (online)	1460-2709
ISSN	1369-3786
DOI	10.1093/mmy/myac054
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Article ; Online: Cross-Sectional Study of Clinical Predictors of Coccidioidomycosis, Arizona, USA

Ferris A. Ramadan / Katherine D. Ellingson / Robert A. Canales / Edward J. Bedrick / John N. Galgiani / Fariba M. Donovan

Emerging Infectious Diseases, Vol 28, Iss 6, Pp 1091-

2022 Volume 1100

Abstract	Demographic and clinical indicators have been described to support identification of coccidioidomycosis; however, the interplay of these conditions has not been explored in a clinical setting. In 2019, we enrolled 392 participants in a cross-sectional study for suspected coccidioidomycosis in emergency departments and inpatient units in Coccidioides-endemic regions. We aimed to develop a predictive model among participants with suspected coccidioidomycosis. We applied a least absolute shrinkage and selection operator to specific coccidioidomycosis predictors and developed univariable and multivariable logistic regression models. Univariable models identified elevated eosinophil count as a statistically significant predictive feature of coccidioidomycosis in both inpatient and outpatient settings. Our multivariable outpatient model also identified rash (adjusted odds ratio 9.74 [95% CI 1.03–92.24]; p = 0.047) as a predictor. Our results suggest preliminary support for developing a coccidioidomycosis prediction model for use in clinical settings.
Keywords	coccidioidomycosis ; Coccidioides ; fungi ; respiratory infections ; Valley fever ; risk factors ; Medicine ; R ; Infectious and parasitic diseases ; RC109-216
Subject code	310
Language	English
Publishing date	2022-06-01T00:00:00Z
Publisher	Centers for Disease Control and Prevention
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The WOPR family protein Ryp1 is a key regulator of gene expression, development, and virulence in the thermally dimorphic fungal pathogen Coccidioides posadasii.

M Alejandra Mandel / Sinem Beyhan / Mark Voorhies / Lisa F Shubitz / John N Galgiani / Marc J Orbach / Anita Sil

PLoS Pathogens, Vol 18, Iss 4, p e

2022 Volume 1009832

Abstract	Coccidioides spp. are mammalian fungal pathogens endemic to the Southwestern US and other desert regions of Mexico, Central and South America, with the bulk of US infections occurring in California and Arizona. In the soil, Coccidioides grows in a hyphal form that differentiates into 3-5 micron asexual spores (arthroconidia). When arthroconidia are inhaled by mammals they undergo a unique developmental transition from polar hyphal growth to isotropic expansion with multiple rounds of nuclear division, prior to segmentation, forming large spherules filled with endospores. Very little is understood about the molecular basis of spherule formation. Here we characterize the role of the conserved transcription factor Ryp1 in Coccidioides development. We show that Coccidioides Δryp1 mutants have altered colony morphology under hypha-promoting conditions and are unable to form mature spherules under spherule-promoting conditions. We analyze the transcriptional profile of wild-type and Δryp1 mutant cells under hypha- and spherule-promoting conditions, thereby defining a set of hypha- or spherule-enriched transcripts ("morphology-regulated" genes) that are dependent on Ryp1 for their expression. Forty percent of morphology-regulated expression is Ryp1-dependent, indicating that Ryp1 plays a dual role in both hyphal and spherule development. Ryp1-dependent transcripts include key virulence factors such as SOWgp, which encodes the spherule outer wall glycoprotein. Concordant with its role in spherule development, we find that the Δryp1 mutant is completely avirulent in the mouse model of coccidioidomycosis, indicating that Ryp1-dependent pathways are essential for the ability of Coccidioides to cause disease. Vaccination of C57BL/6 mice with live Δryp1 spores does not provide any protection from lethal C. posadasii intranasal infection, consistent with our findings that the Δryp1 mutant fails to make mature spherules and likely does not express key antigens required for effective vaccination. Taken together, this work ...
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Subject code	570
Language	English
Publishing date	2022-04-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: A Chronic Murine Disease Model of Coccidioidomycosis Using Coccidioides posadasii, Strain 1038.

Shubitz, Lisa F / Powell, Daniel A / Butkiewicz, Christine D / Lewis, M Lourdes / Trinh, Hien T / Frelinger, Jeffrey A / Orbach, Marc J / Galgiani, John N

The Journal of infectious diseases

2020 Volume 223, Issue 1, Page(s) 166–173

Abstract: ... survival of C57BL/6 (B6) mice. In resistant (B6D2)F1/J mice, lung fungal burdens stabilized by week 4 ...

Abstract	Murine infections with most Coccidioides spp. strains are lethal by 3 weeks, limiting the study of immune responses. Coccidioides posadasii, strain 1038 (Cp1038), while slowly lethal, resulted in protracted survival of C57BL/6 (B6) mice. In resistant (B6D2)F1/J mice, lung fungal burdens stabilized by week 4 without progression through week 16, better modeling human coccidioidal infections after their immunologic control. Immunodeficient tumor necrosis factor (Tnf) α knockout (KO) and interferon (Ifn) γ receptor 1 (Ifn-γr1) KO mice survived a median of 22.5 and 34 days, compared with 70 days in B6 mice (P = .001 and P < .01, respectively), though 14-day lung fungal burden studies showed little difference between Ifn-γr1 KO and B6 mice. B6 mice showed peak concentrations of key inflammatory lung cytokines, including interleukin 6, 23, and 17A, Tnf-α, and Ifn-γ, only after 4 weeks of infection. The slower progression in B6 and the acquired fungal burden stability in B6D2 mice after Cp1038 infection greatly increases the array of possible immunologic studies.
MeSH term(s)	Animals ; Coccidioides/immunology ; Coccidioidomycosis/immunology ; Coccidioidomycosis/microbiology ; Disease Models, Animal ; Lung/microbiology ; Mice ; Mice, Inbred C57BL ; Mice, Knockout
Language	English
Publishing date	2020-07-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	3019-3
ISSN	1537-6613 ; 0022-1899
ISSN (online)	1537-6613
ISSN	0022-1899
DOI	10.1093/infdis/jiaa419
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