Rory Watts

Maternal Intravenous Treatment with either Azithromycin or Solithromycin Clears Ureaplasma parvum from the Amniotic Fluid in an Ovine Model of Intrauterine Infection

ABSTRACT Intrauterine infection with Ureaplasma spp. is strongly associated with preterm birth and adverse neonatal outcomes. We assessed whether combined intraamniotic (IA) and maternal intravenous (IV) treatment with one of two candidate antibiotics, azithromycin (AZ) or solithromycin (SOLI), would eradicate intrauterine Ureaplasma parvum infection in a sheep model of pregnancy. Sheep with singleton pregnancies received an IA injection of U. parvum serovar 3 at 85 days of gestational age (GA). At 120 days of GA, animals (n = 5 to 8/group) received one of the following treatments: (i) maternal IV SOLI with a single IA injection of vehicle (IV SOLI only); (ii) maternal IV SOLI with a single IA injection of SOLI (IV+IA SOLI); (iii) maternal IV AZ and a single IA injection of vehicle (IV AZ only); (iv) maternal IV AZ and a single IA injection of AZ (IV+IA AZ); or (v) maternal IV and single IA injection of vehicle (control). Lambs were surgically delivered at 125 days of GA. Treatment efficacies were assessed by U. parvum culture, quantitative PCR, enzyme-linked immunosorbent assay, and histopathology. Amniotic fluid (AF) from all control animals contained culturable U. parvum. AF, lung, and chorioamnion from all AZ- or SOLI-treated animals (IV only or IV plus IA) were negative for culturable U. parvum. Relative to the results for the control, the levels of expression of interleukin 1β (IL-1β), IL-6, IL-8, and monocyte chemoattractant protein 2 (MCP-2) in fetal skin were significantly decreased in the IV SOLI-only group, the MCP-1 protein concentration in the amniotic fluid was significantly increased in the IV+IA SOLI group, and there was no significant difference in the histological inflammation scoring of lung or chorioamnion among the five groups. In the present study, treatment with either AZ or SOLI (IV only or IV+IA) effectively eradicated macrolide-sensitive U. parvum from the AF. There was no discernible difference in antibiotic therapy efficacy between IV-only and IV+IA treatment regimens relative to the results for the control.

Intrauterine Candida albicans Infection Causes Systemic Fetal Candidiasis with Progressive Cardiac Dysfunction in a Sheep Model of Early Pregnancy

Introduction: Several recent studies have identified a potential role for intrauterine Candida albicans in adverse pregnancy outcomes, including preterm birth. There is, however, a limited understanding of the impact of intrauterine candida infection on fetal well-being in early pregnancy. Using a sheep model of early pregnancy, the aims of this study were to determine (1) the ability of experimentally induced intrauterine C albicans to infect the fetus and (2) whether C albicans exposure in early pregnancy is associated with alterations in fetal cardiac function, as measured by spectral tissue Doppler imaging analysis of fetal cardiac function. Methods: Merino ewes carrying singleton pregnancies at 89 days’ gestation (term is ∼150 days) received C albicans (n = 8) via ultrasound-guided intra-amniotic injection. Saline-exposed fetuses served as controls (n = 6). Spectral tissue Doppler imaging echocardiography and amniotic fluid collection were performed at baseline and 24 and 72 hours after intrauterine C albicans injection. Fetal tissues were collected at postmortem for analysis of infection and inflammation. Results: Relative to saline control, intrauterine C albicans infection resulted in pronounced increases in amniotic fluid tumor necrosis factor α (TNF-α; P < .05) and cytokine/chemokine messenger RNA (interleukin [IL] 1β, IL-6, TNF-α, and monocyte chemoattractant protein 1; P < .05) in the fetal myocardium, lung, skin, and liver at 72 and 96 hours postinfection. Spectral tissue Doppler imaging showed diastolic dysfunction at 24 hours and severe biventricular diastolic dysfunction 72 hours postinfection. Conclusion: Intrauterine C albicans infection in a sheep model of early pregnancy causes systemic fetal candidiasis, which is associated with a robust systemic inflammatory response and progressive cardiac dysfunction detectable by spectral tissue Doppler imaging.

Whole blood flow cytometric analysis of Ureaplasma-stimulated monocytes from pregnant women

We hypothesised that circulating monocytes of women with vaginal colonisation with Ureaplasma spp., genital microorganisms known to cause inflammation-driven preterm birth, would elicit a tolerised cytokine response to subsequent in vitro Ureaplasma parvum serovar 3 (UpSV3) stimulation. Using multi-parameter flow cytometry, we found no differences with regard to maternal colonisation status in the frequency of TNF-α-, IL-6-, IL-8- and IL-1β-expressing monocytes in response to subsequent UpSV3 stimulation (P > 0.10 for all cytokines). We conclude that vaginal Ureaplasma spp. colonisation does not specifically tolerise monocytes of pregnant women towards decreased responses to subsequent stimulation.

Economic Evaluations of Pathology Tests, 2010-2015: A Scoping Review

BACKGROUND Concerns about pathology testing such as the value provided by new tests and the potential for inappropriate utilization have led to a greater need to assess costs and benefits. Economic evaluations are a formal method of analyzing costs and benefits, yet for pathology tests, questions remain about the scope and quality of the economic evidence. OBJECTIVE To describe the extent and quality of published evidence provided by economic evaluations of pathology tests from 2010 to 2015. METHODS Economic evaluations relating to pathology tests from 2010 to 2015 were reviewed. Eight databases were searched for published studies, and details recorded for the country, clinical focus, type of testing, and consideration of sensitivity, specificity, and false test results. The reporting quality of studies was assessed using the Consolidated Health Economic Evaluation Reporting Standards checklist and cost-effectiveness ratios were analyzed for publication bias. RESULTS We found 356 economic evaluations of pathology tests, most of which regarded developed countries. The most common economic evaluations were cost-utility analyses and the most common clinical focus was infectious diseases. More than half of the studies considered sensitivity and specificity, but few studies considered the impact of false test results. The average Consolidated Health Economic Evaluation Reporting Standards checklist score was 17 out of 24. Cost-utility ratios were commonly less than

Disease control programme support costs: an update of WHO-CHOICE methodology, price databases and quantity assumptions

10,000/quality-adjusted life-year or more than

T cell cytokine responses to stimulation with Ureaplasma parvum in pregnancy

200,000/quality-adjusted life-year. CONCLUSIONS The number of economic evaluations of pathology tests has increased in recent years, but the rate of increase has plateaued. Furthermore, the quality of studies in the past 5 years was highly variable, and there is some question of publication bias in reporting cost-effectiveness ratios.

Repeated maternal intramuscular or intraamniotic erythromycin incompletely resolves intrauterine Ureaplasma parvum infection in a sheep model of pregnancy

BackgroundEstimating health care costs, either in the context of understanding resource utilization in the implementation of a health plan, or in the context of economic evaluation, has become a common activity of health planners, health technology assessment agencies and academic groups. However, data sources for costs outside of direct service delivery are often scarce. WHO-CHOICE produces global price databases and guidance on quantity assumptions to support country level costing exercises. This paper presents updates to the WHO-CHOICE methodology and price databases for programme costs.MethodsWe collated publicly available databases for 14 non-traded cost variables, as well as a set of traded items used within health systems (traded goods are those which can be purchased from anywhere in the world, whereas non-traded goods are those which must be produced locally, such as human resources). Within each of the variables, missing data was present for some proportion of the WHO member states. For each variables statistical or econometric models were used to model prices for each of the 194 WHO member states in 2010 International Dollars. Literature reviews were used to update quantity assumptions associated with each variable to contribute to the support costs of disease control programmes.ResultsA full database of prices for disease control programme support costs is available for country-specific costing purposes. Human resources are the largest driver of disease control programme support costs, followed by supervision costs.ConclusionsDespite major advances in the availability of data since the previous version of this work, there are still some limitations in data availability to respond to the needs of those wishing to develop cost and cost-effectiveness estimates. Greater attention to programme support costs in cost data collection activities would contribute to an understanding of how these costs contribute to quality of health service delivery and should be encouraged.

Ureaplasma parvum genotype, combined vaginal colonisation with Candida albicans, and spontaneous preterm birth in an Australian cohort of pregnant women

UNLABELLED Ureaplasma spp. are a common vaginal microorganism causally linked to inflammation-driven preterm birth (PTB). The nature of the immune response to Ureaplasma spp. may influence PTB risk. This study sought to define maternal T cell cytokine responses to in vitro stimulation with Ureaplasma parvum serovar 3 (UpSV3) in vaginally colonised (UP+) and non-colonised (UP-) pregnant women. Whole blood flow cytometry demonstrated an increase (p=0.027) in the baseline frequency of IFNγ-positive CD3(+)CD4(-)(CD8(+)) T cells in UP+ women. UpSV3 stimulation resulted in a significant and specific increase (p=0.001) in the frequency of IFNγ-positive CD3(+)CD4(-)(CD8(+)) T cells, regardless of vaginal colonisation status. UpSV3 stimulation also increased the frequency of IFNγ-positive CD3(+)CD4(+) T cells, particularly in the UP+ group (p=0.003). This is the first published study to examine T cell responses to Ureaplasma spp. EXPOSURE Future appropriately-powered studies are needed to assess whether insufficient priming or a loss of tolerance to Ureaplasma spp. is occurring in UP+ women at risk of PTB.