Poly-immunoglobulin receptor-mediated transport of IgA into the male genital tract is important for clearance of chlamydia muridarum infection

Problem: Chlamydia trachomatis is the most common sexually transmitted infection worldwide. While infection in females requires a Th1 response for clearance, such a response in males may disrupt the immune privileged nature of the male reproductive tract, potentially contributing to infertility. Method of study: We investigated the role of IgA in protection against an intrapenile Chlamydia muridarum infection of C57BL/6 and pIgR−/− mice. Results: Here, we show that the poly immunoglobulin receptor is the main pathway for IgA transport into the male reproductive tract. The high levels of IgA seen in prostatic fluid of wild-type mice correlate with reduction in chlamydial infection both in vitro and in vivo. Conclusion: These findings indicate that a Chlamydia vaccine that induces neutralizing IgA in the prostate will aid in the protection against infection in males.

Setting hospital infection control policy : a decision-making framework incorporating health economics and healthcare epidemiology

Background: Reducing rates of healthcare acquired infection has been identified by the Australian Commission on Safety and Quality in Health Care as a national priority. One of the goals is the prevention of central venous catheter-related bloodstream infection (CR-BSI). At least 3,500 cases of CR-BSI occur annually in Australian hospitals, resulting in unnecessary deaths and costs to the healthcare system between $25.7 and $95.3 million. Two approaches to preventing these infections have been proposed: use of antimicrobial catheters (A-CVCs); or a catheter care and management ‘bundle’. Given finite healthcare budgets, decisions about the optimal infection control policy require consideration of the effectiveness and value for money of each approach. Objectives: The aim of this research is to use a rational economic framework to inform efficient infection control policy relating to the prevention of CR-BSI in the intensive care unit. It addresses three questions relating to decision-making in this area: 1. Is additional investment in activities aimed at preventing CR-BSI an efficient use of healthcare resources? 2. What is the optimal infection control strategy from amongst the two major approaches that have been proposed to prevent CR-BSI? 3. What uncertainty is there in this decision and can a research agenda to improve decision-making in this area be identified? Methods: A decision analytic model-based economic evaluation was undertaken to identify an efficient approach to preventing CR-BSI in Queensland Health intensive care units. A Markov model was developed in conjunction with a panel of clinical experts which described the epidemiology and prognosis of CR-BSI. The model was parameterised using data systematically identified from the published literature and extracted from routine databases. The quality of data used in the model and its validity to clinical experts and sensitivity to modelling assumptions was assessed. Two separate economic evaluations were conducted. The first evaluation compared all commercially available A-CVCs alongside uncoated catheters to identify which was cost-effective for routine use. The uncertainty in this decision was estimated along with the value of collecting further information to inform the decision. The second evaluation compared the use of A-CVCs to a catheter care bundle. We were unable to estimate the cost of the bundle because it is unclear what the full resource requirements are for its implementation, and what the value of these would be in an Australian context. As such we undertook a threshold analysis to identify the cost and effectiveness thresholds at which a hypothetical bundle would dominate the use of A-CVCs under various clinical scenarios. Results: In the first evaluation of A-CVCs, the findings from the baseline analysis, in which uncertainty is not considered, show that the use of any of the four A-CVCs will result in health gains accompanied by cost-savings. The MR catheters dominate the baseline analysis generating 1.64 QALYs and cost-savings of $130,289 per 1.000 catheters. With uncertainty, and based on current information, the MR catheters remain the optimal decision and return the highest average net monetary benefits ($948 per catheter) relative to all other catheter types. This conclusion was robust to all scenarios tested, however, the probability of error in this conclusion is high, 62% in the baseline scenario. Using a value of $40,000 per QALY, the expected value of perfect information associated with this decision is $7.3 million. An analysis of the expected value of perfect information for individual parameters suggests that it may be worthwhile for future research to focus on providing better estimates of the mortality attributable to CR-BSI and the effectiveness of both SPC and CH/SSD (int/ext) catheters. In the second evaluation of the catheter care bundle relative to A-CVCs, the results which do not consider uncertainty indicate that a bundle must achieve a relative risk of CR-BSI of at least 0.45 to be cost-effective relative to MR catheters. If the bundle can reduce rates of infection from 2.5% to effectively zero, it is cost-effective relative to MR catheters if national implementation costs are less than $2.6 million ($56,610 per ICU). If the bundle can achieve a relative risk of 0.34 (comparable to that reported in the literature) it is cost-effective, relative to MR catheters, if costs over an 18 month period are below $613,795 nationally ($13,343 per ICU). Once uncertainty in the decision is considered, the cost threshold for the bundle increases to $2.2 million. Therefore, if each of the 46 Level III ICUs could implement an 18 month catheter care bundle for less than $47,826 each, this approach would be cost effective relative to A-CVCs. However, the uncertainty is substantial and the probability of error in concluding that the bundle is the cost-effective approach at a cost of $2.2 million is 89%. Conclusions: This work highlights that infection control to prevent CR-BSI is an efficient use of healthcare resources in the Australian context. If there is no further investment in infection control, an opportunity cost is incurred, which is the potential for a more efficient healthcare system. Minocycline/rifampicin catheters are the optimal choice of antimicrobial catheter for routine use in Australian Level III ICUs, however, if a catheter care bundle implemented in Australia was as effective as those used in the large studies in the United States it would be preferred over the catheters if it was able to be implemented for less than $47,826 per Level III ICU. Uncertainty is very high in this decision and arises from multiple sources. There are likely greater costs to this uncertainty for A-CVCs, which may carry hidden costs, than there are for a catheter care bundle, which is more likely to provide indirect benefits to clinical practice and patient safety. Research into the mortality attributable to CR-BSI, the effectiveness of SPC and CH/SSD (int/ext) catheters and the cost and effectiveness of a catheter care bundle in Australia should be prioritised to reduce uncertainty in this decision. This thesis provides the economic evidence to inform one area of infection control, but there are many other infection control decisions for which information about the cost-effectiveness of competing interventions does not exist. This work highlights some of the challenges and benefits to generating and using economic evidence for infection control decision-making and provides support for commissioning more research into the cost-effectiveness of infection control.

HtrA, RseP, and Tsp do not elicit a pathology related serum IgG response during sexually transmitted infection with Chlamydia trachomatis

Chlamydia trachomatis sexually transmitted infection can cause serious reproductive morbidities. This study determined the prevalence of serum IgG response to C. trachomatis putative stress response proteins in females to test for an association with genital tract pathology. There was no significant association of serum IgG to HtrA, Tsp, or RseP with infection or pathology. cHSP60 serum IgG prevalence was significantly associated with infection compared to negative (infertile) controls (p = 0.002), but not with upper genital tract pathology. Serum IgG1-4 antibody subclasses reactive with the antigens was not significantly different between cohorts, although different responses to each antigen were detected.

Changes in Level of Virus Accumulation and Incidence of Infection are Critical in the Characterization of Rice Tungro Bacilliform Virus (RTBV) Resistance in Rice

Analysis by enzyme-linked immunosorbent assay showed that Rice tungro bacilliform virus (RTBV) accumulated in a cyclic pattern from early to late stages of infection in tungro-susceptible variety, Taichung Native 1 (TN1), and resistant variety, Balimau Putih, singly infected with RTBV or co-infected with RTBV+Rice tungro spherical virus (RTSV). These changes in virus accumulation resulted in differences in RTBV levels and incidence of infection. The virus levels were expressed relative to those of the susceptible variety and the incidence of infection was assessed at different weeks after inoculation. At a particular time point, RTBV levels in TN1 or Balimau Putih singly infected with RTBV were not significantly different from the virus level in plants co-infected with RTBV+RTSV. The relative RTBV levels in Balimau Putih either singly infected with RTBV or co-infected with RTBV+RTSV were significantly lower than those in TN1. The incidence of RTBV infection varied at different times in Balimau Putih but not in TN1, and to determine the actual infection, the number of plants that became infected at least once anytime during the 4wk observation period was considered. Considering the changes in RTBV accumulation, new parameters for analyzing RTBV resistance were established. Based on these parameters, Balimau Putih was characterized having resistance to virus accumulation although the actual incidence of infection was >75%.

Excess length of stay due to central line–associated bloodstream infection in intensive care units in Argentina, Brazil, and Mexico

Objective.To estimate the excess length of stay in an intensive care unit (ICU) due to a central line–associated bloodstream infection (CLABSI), using a multistate model that accounts for the timing of infection. Design.A cohort of 3,560 patients followed up for 36,806 days in ICUs. Setting.Eleven ICUs in 3 Latin American countries: Argentina, Brazil, and Mexico. Patients.All patients admitted to the ICU during a defined time period with a central line in place for more than 24 hours. Results.The average excess length of stay due to a CLABSI increased in 10 of 11 ICUs and varied from −1.23 days to 4.69 days. A reduction in length of stay in Mexico was probably caused by an increased risk of death due to CLABSI, leading to shorter times to death. Adjusting for patient age and Average Severity of Illness Score tended to increase the estimated excess length of stays due to CLABSI. Conclusions.CLABSIs are associated with an excess length of ICU stay. The average excess length of stay varies between ICUs, most likely because of the case‐mix of admissions and differences in the ways that hospitals deal with infections.

Using economic data to reduce healthcare-acquired infection

In this issue Burns et al. report an estimate of the economic loss to Auckland City Hospital from cases of healthcare-associated bloodstream infection. They show that patients with infection stay longer in hospital and this must impose an opportunity cost because beds are blocked. Harder to measure costs fall on patients, their families and non-acute health services. Patients face some risk of dying from the infection.

Chlamydial infection of immune cells : altered function and implications for disease

Chlamydia trachomatis is an obligate intracellular bacterial pathogen that infects the genital and ocular mucosa of humans, causing infections that can lead to pelvic inflammatory disease, infertility, and blinding trachoma. C. pneumoniae is a respiratory pathogen that is the cause of 12–15% of community-acquired pneumonia. Both chlamydial species were believed to be restricted to the epithelia of the genital, ocular, and respiratory mucosa; however, increasing evidence suggests that both these pathogens can be isolated from peripheral blood of both healthy individuals and patients with inflammatory conditions such as coronary artery disease and asthma. Chlamydia can also be isolated from brain tissues of patients with degenerative neurological disorders such as Alzheimer’s disease and multiple sclerosis, and also from certain lymphomas. An increasing number of in vitro studies suggest that some chlamydial species can infect immune cells, at least at low levels. These infections may alter immune cell function in a way that promotes chlamydial persistence in the host and contributes to the progression of several chronic inflammatory diseases. In this paper, we review the evidence for the growth of Chlamydia in immune cells, particularly monocytes/macrophages and dendritic cells, and describe how infection may affect the function of these cells.

Chlamydia muridarum major outer membrane protein-specific antibodies inhibit in vitro infection but enhance pathology in vivo

PROBLEM Chlamydia trachomatis is a significant worldwide health problem, and the often-asymptomatic disease can result in infertility. To develop a successful vaccine, a complete understanding of the immune response to chlamydial infection and development of genital tract pathology is required. METHOD OF STUDY We utilized the murine genital model of chlamydial infection. Mice were immunized with chlamydial major outer membrane protein, and vaginal lavage was assessed for the presence of neutralizing antibodies. These samples were then pre-incubated with Chlamydia muridarum and administered to the vaginal vaults of immune-competent female BALB/c mice to determine the effect on infection. RESULTS The administration of C. muridarum in conjunction with neutralizing antibodies reduced the numbers of mice infected, but a surprising finding was that this accelerated the development of severe oviduct pathology. CONCLUSION Antibodies play an under-recognized role in chlamydial infection and pathology development, which possibly involves interaction with Th1 immunity.

Maternal administration of erythromycin fails to eradicate intrauterine ureaplasma infection in an ovine model

Erythromycin is the standard antibiotic used for treatment of Ureaplasma species during 3 pregnancy; however, maternally administered erythromycin may be ineffective at eliminating 4 intra-amniotic ureaplasma infections. We asked if erythromycin would eradicate intra-amniotic 5 ureaplasma infections in pregnant sheep. At 50 days of gestation (d, term=150d) pregnant ewes 6 received intra-amniotic injections of erythromycin-sensitive U. parvum serovar 3 (n=16) or 10B 7 medium (n=16). At 100d, amniocentesis was performed; five fetal losses (ureaplasma group: 8 n=4; 10B group: n=1) had occurred by this time. Remaining ewes were allocated into treatment 9 subgroups: medium only (M, n=7); medium and erythromycin (M/E, n=8); ureaplasma only (Up, 10 n=6) or ureaplasma and erythromycin (Up/E, n=6). Erythromycin was administered intra11 muscularly (500 mg), eight-hourly for four days (100d-104d). Amniotic fluid samples were 12 collected at 105d. At 125d preterm fetuses were surgically delivered and specimens were 13 collected for culture and histology. Erythromycin was quantified in amniotic fluid by liquid 14 chromatography-mass spectrometry. Ureaplasmas were isolated from the amniotic fluid, 15 chorioamnion and fetal lung of animals from the Up and Up/E groups, however, the numbers of 16 U. parvum recovered were not different between these groups. Inflammation in the 17 chorioamnion, cord and fetal lung was increased in ureaplasma-exposed animals compared to 18 controls, but was not different between the Up and Up/E groups. Erythromycin was detected in 19 amniotic fluid samples, although concentrations were low (<10-76 ng/mL). This study 20 demonstrates that maternally administered erythromycin does not eradicate chronic, intra- amniotic ureaplasma infections or improve fetal outcomes in an ovine model, potentially due to 22 the poor placental passage of erythromycin.

A mathematical model of chlamydial infection incorporating movement of chlamydial particles

We present a spatiotemporal mathematical model of chlamydial infection, host immune response and spatial movement of infectious particles. The re- sulting partial differential equations model both the dynamics of the infection and changes in infection profile observed spatially along the length of the host genital tract. This model advances previous chlamydia modelling by incorporating spatial change, which we also demonstrate to be essential when the timescale for movement of infectious particles is equal to, or shorter than, the developmental cycle timescale. Numerical solutions and model analysis are carried out, and we present a hypothesis regarding the potential for treatment and prevention of infection by increasing chlamydial particle motility.

Resident-funded retirement village valuations : complications with the application of the DCF

Retirement village assets are different from traditional residential assets due to their operation in accordance with statutory legislation. Designed for independent living, retirement villages provide either detached or semi-detached residential dwellings with car parking and small private yards with community facilities providing a shared congregational area for village activities and socialising. In essence, the village operator provides the land and buildings to the residents who pay an amount on entry for the right of occupation. On departure from the units an agreed proportion of either the original purchase price or the sale price is paid to the outgoing resident. As ongoing levies are typically offset by ongoing operational expenses the market value of the operator's interest in the retirement village is therefore predominantly based upon the estimated future income from deferred management fees and capital gain upon roll-over receivable by the operator in accordance with the respective residency agreements. Given the lumpiness of these payments, there is general acceptance that the most appropriate approach to valuation is through discounted cash flow (DCF) analysis. There is however inconsistency between valuers across Australia in how they undertake their DCF analysis, leading to differences in reported values and subsequent confusion among users of valuation services. To give guidance to valuers and enhance confidence from users of valuation services this paper investigates the five major elements of DCF methodology, namely cash flows, escalation factors, holding period, terminal value and discount rate.