Adherence, adaptation and acceptance of elderly chronic heart failure patients to receiving healthcare via telephone-monitoring

Background: Although the potential to reduce hospitalisation and mortality in chronic heart failure (CHF) is well reported, the feasibility of receiving healthcare by structured telephone support or telemonitoring is not. Aims: To determine; adherence, adaptation and acceptability to a national nurse-coordinated telephone-monitoring CHF management strategy. The Chronic Heart Failure Assistance by Telephone Study (CHAT). Methods: Triangulation of descriptive statistics, feedback surveys and qualitative analysis of clinical notes. Cohort comprised of standard care plus intervention (SC + I) participants who completed the first year of the study. Results: 30 GPs (70% rural) randomised to SC + I recruited 79 eligible participants, of whom 60 (76%) completed the full 12 month follow-up period. During this time 3619 calls were made into the CHAT system (mean 45.81 SD ± 79.26, range 0-369), Overall there was an adherence to the study protocol of 65.8% (95% CI 0.54-0.75; p = 0.001) however, of the 60 participants who completed the 12 month follow-up period the adherence was significantly higher at 92.3% (95% CI 0.82-0.97, p ≤ 0.001). Only 3% of this elderly group (mean age 74.7 ±9.3 years) were unable to learn or competently use the technology. Participants rated CHAT with a total acceptability rate of 76.45%. Conclusion: This study shows that elderly CHF patients can adapt quickly, find telephone-monitoring an acceptable part of their healthcare routine, and are able to maintain good adherence for a least 12 months. © 2007.

Projecting Computational Sense of Self: A Study of Transition in a Chronic Illness Online Community

We report on analysis of discussions in an online community of people with chronic illness using socio-cognitively motivated, automatically produced semantic spaces. The analysis aims to further the emerging theory of "transition" (how people can learn to incorporate the consequences of illness into their lives). An automatically derived representation of sense of self for individuals is created in the semantic space by the analysis of the email utterances of the community members. The movement over time of the sense of self is visualised, via projection, with respect to axes of "ordinariness" and "extra-ordinariness". Qualitative evaluation shows that the visualisation is paralleled by the transitions of people during the course of their illness. The research aims to progress tools for analysis of textual data to promote greater use of tacit knowledge as found in online virtual communities. We hope it also encourages further interest in representation of sense-of-self.

The role of the multiple banded antigen of ureaplasma parvum in intra-amniotic infection : major virulence factor or decoy?

The multiple banded antigen (MBA) is a predicted virulence factor of Ureaplasma species. Antigenic variation of the MBA is a potential mechanism by which ureaplasmas avoid immune recognition and cause chronic infections of the upper genital tract of pregnant women. We tested whether the MBA is involved in the pathogenesis of intra-amniotic infection and chorioamnionitis by injecting virulent or avirulent-derived ureaplasma clones (expressing single MBA variants) into the amniotic fluid of pregnant sheep. At 55 days of gestation pregnant ewes (n = 20) received intra-amniotic injections of virulent-derived or avirulent-derived U. parvum serovar 6 strains (2×104 CFU), or 10B medium (n = 5). Amniotic fluid was collected every two weeks post-infection and fetal tissues were collected at the time of surgical delivery of the fetus (140 days of gestation). Whilst chronic colonisation was established in the amniotic fluid of animals infected with avirulent-derived and virulent-derived ureaplasmas, the severity of chorioamnionitis and fetal inflammation was not different between these groups (p>0.05). MBA size variants (32–170 kDa) were generated in vivo in amniotic fluid samples from both the avirulent and virulent groups, whereas in vitro antibody selection experiments led to the emergence of MBA-negative escape variants in both strains. Anti-ureaplasma IgG antibodies were detected in the maternal serum of animals from the avirulent (40%) and virulent (55%) groups, and these antibodies correlated with increased IL-1β, IL-6 and IL-8 expression in chorioamnion tissue (p<0.05). We demonstrate that ureaplasmas are capable of MBA phase variation in vitro; however, ureaplasmas undergo MBA size variation in vivo, to potentially prevent eradication by the immune response. Size variation of the MBA did not correlate with the severity of chorioamnionitis. Nonetheless, the correlation between a maternal humoral response and the expression of chorioamnion cytokines is a novel finding. This host response may be important in the pathogenesis of inflammation-mediated adverse pregnancy outcomes.

A longitudinal assessment of chronic wound fluid to detect biochemical indicators of healing

Chronic venous leg ulcers are a detrimental health issue plaguing our society, resulting in long term pain, immobility and decreased quality of life for a large proportion of sufferers. The frequency of these chronic wounds has led current research to focus on the wound environment to provide important information regarding the prolonged, fluctuated or static healing patterns of these wounds. Disruption to the normal wound healing process results in release of multiple factors in the wound environment that could correlate to wound chronicity. These biochemical factors can often be detected through non-invasively sampling chronic wound fluid (CWF) from the site of injury. Of note, whilst there are numerous studies comparing acute and chronic wound fluids, there have not been any reports in the literature employing a longitudinal study in order to track biochemical changes in wound fluid as patients transition from a non-healing to healed state. Initially the objective of this study was to identify biochemical changes in CWF associated with wound healing using a proteomic approach. The proteomic approach incorporated a multi-dimensional liquid chromatography fractionation technique coupled with mass spectrometry (MS) to enable identification of proteins present in lower concentrations in CWF. Not surprisingly, many of the proteins identified in wound fluid were acute phase proteins normally expressed during the inflammatory phase of healing. However, the number of proteins positively identified by MS was quite low. This was attributed to the diverse range in concentration of protein species in CWF making it challenging to detect the diagnostically relevant low molecular weight proteins. In view of this, SELDI-TOF MS was also explored as a means to target low molecular weight proteins in sequential patient CWF samples during the course of healing. Unfortunately, the results generated did not yield any peaks of interest that were altered as wounds transitioned to a healed state. During the course of proteomic assessment of CWF, it became evident that a fraction of non-proteinaceous compounds strongly absorbed at 280 nm. Subsequent analyses confirmed that most of these compounds were in fact part of the purine catabolic pathway, possessing distinctive aromatic rings and which results in high absorbance at 254 nm. The accumulation of these purinogenic compounds in CWF suggests that the wound bed is poorly oxygenated resulting in a switch to anaerobic metabolism and consequently ATP breakdown. In addition, the presence of the terminal purine catabolite, uric acid (UA), indicates that the enzyme xanthine oxidoreductase (XOR) catalyses the reaction of hypoxanthine to xanthine and finally to UA. More importantly, the studies provide evidence for the first time of the exogenous presence of XOR in CWF. XOR is the only enzyme in humans capable of catalysing the production of UA in conjunction with a burst of the highly reactive superoxide radical and other oxidants like H2O2. Excessive release of these free radicals in the wound environment can cause cellular damage disrupting the normal wound healing process. In view of this, a sensitive and specific assay was established for monitoring low concentrations of these catabolites in CWF. This procedure involved combining high performance liquid chromatography (HPLC) with tandem mass spectrometry and multiple reaction monitoring (MRM). This application was selective, using specific MRM transitions and HPLC separations for each analyte, making it ideal for the detection and quantitation of purine catabolites in CWF. The results demonstrated that elevated levels of UA were detected in wound fluid obtained from patients with clinically worse ulcers. This suggests that XOR is active in the wound site generating significant amounts of reactive oxygen species (ROS). In addition, analysis of the amount of purine precursors in wound fluid revealed elevated levels of purine precursors in wound fluid from patients with less severe ulcers. Taken together, the results generated in this thesis suggest that monitoring changes of purine catabolites in CWF is likely to provide valuable information regarding the healing patterns of chronic venous leg ulcers. XOR catalysis of purine precursors not only provides a method for monitoring the onset, prognosis and progress of chronic venous leg ulcers, but also provides a potential therapeutic target by inhibiting XOR, thus blocking UA and ROS production. Targeting a combination of these purinogenic compounds and XOR could lead to the development of novel point of care diagnostic tests. Therefore, further investigation of these processes during wound healing will be worthwhile and may assist in elucidating the pathogenesis of this disease state, which in turn may lead to the development of new diagnostics and therapies that target these processes.

Modelling the interaction of keratinocytes and fibroblasts during normal and abnormal wound healing processes

The crosstalk between fibroblasts and keratinocytes is a vital component of the wound healing process, and involves the activity of a number of growth factors and cytokines. In this work, we develop a mathematical model of this crosstalk in order to elucidate the effects of these interactions on the regeneration of collagen in a wound that heals by second intention. We consider the role of four components that strongly affect this process: transforming growth factor-beta, platelet-derived growth factor, interleukin-1 and keratinocyte growth factor. The impact of this network of interactions on the degradation of an initial fibrin clot, as well as its subsequent replacement by a matrix that is mainly comprised of collagen, is described through an eight-component system of nonlinear partial differential equations. Numerical results, obtained in a two-dimensional domain, highlight key aspects of this multifarious process such as reepithelialisation. The model is shown to reproduce many of the important features of normal wound healing. In addition, we use the model to simulate the treatment of two pathological cases: chronic hypoxia, which can lead to chronic wounds; and prolonged inflammation, which has been shown to lead to hypertrophic scarring. We find that our model predictions are qualitatively in agreement with previously reported observations, and provide an alternative pathway for gaining insight into this complex biological process.

Do anti-inflammatory agents promote linear ablation lesion discontinuities? : an electrophysiological examination

Background: Catheter ablation for atrial fibrillation (AF) is more efficacious than antiarrhythmic therapy. Post ablation recurrences reduce ablation effectiveness and are contributed by lesion discontinuity in the fibrotic linear ablation lesions. The anti-fibrotic role of statins in reducing AF is being assessed in current trials. By reducing the chronic pathological fibrosis that occurs in AF they may reduce AF. However if statins also have an effect on the acute therapeutic fibrosis of an ablation, this could exacerbate lesion discontinuity and AF recurrence. We tested the hypothesis that statins attenuate ablation lesion continuity in a recognised pig atrial linear ablation model. Aims: To assess whether Atorvastatin diminishes the bi-directional conduction block produced by a linear atrial ablation lesion. Methods: Sixteen pigs were randomised to statin (n=8) or placebo (n=8) with drug pre-treatment for 3 days and a further 4 weeks. At initial electrophysiological study (EPS1) 3D right atrium (RA) mapping and a vertical ablation linear lesion in the posterior RA with bidirectional conduction block were completed (Gepstein Circ 1999). Follow-up electrophysiological assessment (EPS2) at 28 days assessed bidirectional conduction block maintenance. Results: Data of 15/16 (statin=7) pigs were analysed. Mean lesion length was 3.7 ± 0.8cm with a mean of 17.9 ± 5.7 lesion applications. Bi-directional conduction block was confirmed in 15/15 pigs (100%) at EPS1 and EPS2. Conclusions: Atorvastatin did not affect ablation lesion continuity in this pig atrial linear ablation model. If patients are on long-term statins for AF reduction, periablation cessation is probably not necessary.

The duplicitous nature of inflammation in wound repair

Skin plays a key role in protecting the body from the onslaught of pathogens and toxins we meet during our lifetime; thus, out of necessity, we have developed a rapid repair mechanism that quickly plugs any holes in this vital organ. Upon injury, a series of highly coordinated overlapping events, that include inflammatory, proliferation and maturation phases, result in the hasty closure of the wound and restoration of skin integrity. Over the past decade it has become clear that a number of immune cells that regulate the inflammatory phase, whilst important for removal of invading pathogens, are not necessary for repair and in fact may be responsible for the subsequent scar formation that seems to have resulted from having such a rapid repair process. The magnitude and length of inflammation in the wound not only appears to dictate the extent of scar formation but also in some cases may even prevent wound closure. In this review we will explore the two sides of inflammation in wound healing and review current and future drug therapies that target inflammation to modulate the healing outcome.

The relationship between chronic disease self-efficacy and nutritional status, functional ability and quality of life in older adults at risk of hospital readmission

Background and significance: Older adults with chronic diseases are at increasing risk of hospital admission and readmission. Approximately 75% of adults have at least one chronic condition, and the odds of developing a chronic condition increases with age. Chronic diseases consume about 70% of the total Australian health expenditure, and about 59% of hospital events for chronic conditions are potentially preventable. These figures have brought to light the importance of the management of chronic disease among the growing older population. Many studies have endeavoured to develop effective chronic disease management programs by applying social cognitive theory. However, limited studies have focused on chronic disease self-management in older adults at high risk of hospital readmission. Moreover, although the majority of studies have covered wide and valuable outcome measures, there is scant evidence on examining the fundamental health outcomes such as nutritional status, functional status and health-related quality of life. Aim: The aim of this research was to test social cognitive theory in relation to self-efficacy in managing chronic disease and three health outcomes, namely nutritional status, functional status, and health-related quality of life, in older adults at high risk of hospital readmission. Methods: A cross-sectional study design was employed for this research. Three studies were undertaken. Study One examined the nutritional status and validation of a nutritional screening tool; Study Two explored the relationships between participants. characteristics, self-efficacy beliefs, and health outcomes based on the study.s hypothesized model; Study Three tested a theoretical model based on social cognitive theory, which examines potential mechanisms of the mediation effects of social support and self-efficacy beliefs. One hundred and fifty-seven patients aged 65 years and older with a medical admission and at least one risk factor for readmission were recruited. Data were collected from medical records on demographics, medical history, and from self-report questionnaires. The nutrition data were collected by two registered nurses. For Study One, a contingency table and the kappa statistic was used to determine the validity of the Malnutrition Screening Tool. In Study Two, standard multiple regression, hierarchical multiple regression and logistic regression were undertaken to determine the significant influential predictors for the three health outcome measures. For Study Three, a structural equation modelling approach was taken to test the hypothesized self-efficacy model. Results: The findings of Study One suggested that a high prevalence of malnutrition continues to be a concern in older adults as the prevalence of malnutrition was 20.6% according to the Subjective Global Assessment. Additionally, the findings confirmed that the Malnutrition Screening Tool is a valid nutritional screening tool for hospitalized older adults at risk of readmission when compared to the Subjective Global Assessment with high sensitivity (94%), and specificity (89%) and substantial agreement between these two methods (k = .74, p < .001; 95% CI .62-.86). Analysis data for Study Two found that depressive symptoms and perceived social support were the two strongest influential factors for self-efficacy in managing chronic disease in a hierarchical multiple regression. Results of multivariable regression models suggested advancing age, depressive symptoms and less tangible support were three important predictors for malnutrition. In terms of functional status, a standard regression model found that social support was the strongest predictor for the Instrumental Activities of Daily Living, followed by self-efficacy in managing chronic disease. The results of standard multiple regression revealed that the number of hospital readmission risk factors adversely affected the physical component score, while depressive symptoms and self-efficacy beliefs were two significant predictors for the mental component score. In Study Three, the results of the structural equation modelling found that self-efficacy partially mediated the effect of health characteristics and depression on health-related quality of life. The health characteristics had strong direct effects on functional status and body mass index. The results also indicated that social support partially mediated the relationship between health characteristics and functional status. With regard to the joint effects of social support and self-efficacy, social support fully mediated the effect of health characteristics on self-efficacy, and self-efficacy partially mediated the effect of social support on functional status and health-related quality of life. The results also demonstrated that the models fitted the data well with relative high variance explained by the models, implying the hypothesized constructs under discussion were highly relevant, and hence the application for social cognitive theory in this context was supported. Conclusion: This thesis highlights the applicability of social cognitive theory on chronic disease self-management in older adults at risk of hospital readmission. Further studies are recommended to validate and continue to extend the development of social cognitive theory on chronic disease self-management in older adults to improve their nutritional and functional status, and health-related quality of life.

Ureaplasma parvum : understanding the complexities of intra-amniotic infection in an ovine model

The human Ureaplasma species are the most frequently isolated bacteria from the upper genital tract of pregnant women and can cause clinically asymptomatic, intra-uterine infections, which are difficult to treat with antimicrobials. Ureaplasma infection of the upper genital tract during pregnancy has been associated with numerous adverse outcomes including preterm birth, chorioamnionitis and neonatal respiratory diseases. The mechanisms by which ureaplasmas are able to chronically colonise the amniotic fluid and avoid eradication by (i) the host immune response and (ii) maternally-administered antimicrobials, remain virtually unexplored. To address this gap within the literature, this study investigated potential mechanisms by which ureaplasmas are able to cause chronic, intra-amniotic infections in an established ovine model. In this PhD program of research the effectiveness of standard, maternal erythromycin for the treatment of chronic, intra-amniotic ureaplasma infections was evaluated. At 55 days of gestation pregnant ewes received an intra-amniotic injection of either: a clinical Ureaplasma parvum serovar 3 isolate that was sensitive to macrolide antibiotics (n = 16); or 10B medium (n = 16). At 100 days of gestation, ewes were then randomised to receive either maternal erythromycin treatment (30 mg/kg/day for four days) or no treatment. Ureaplasmas were isolated from amniotic fluid, chorioamnion, umbilical cord and fetal lung specimens, which were collected at the time of preterm delivery of the fetus (125 days of gestation). Surprisingly, the numbers of ureaplasmas colonising the amniotic fluid and fetal tissues were not different between experimentally-infected animals that received erythromycin treatment or infected animals that did not receive treatment (p > 0.05), nor were there any differences in fetal inflammation and histological chorioamnionitis between these groups (p > 0.05). These data demonstrate the inability of maternal erythromycin to eradicate intra-uterine ureaplasma infections. Erythromycin was detected in the amniotic fluid of animals that received antimicrobial treatment (but not in those that did not receive treatment) by liquid chromatography-mass spectrometry; however, the concentrations were below therapeutic levels (<10 – 76 ng/mL). These findings indicate that the ineffectiveness of standard, maternal erythromycin treatment of intra-amniotic ureaplasma infections may be due to the poor placental transfer of this drug. Subsequently, the phenotypic and genotypic characteristics of ureaplasmas isolated from the amniotic fluid and chorioamnion of pregnant sheep after chronic, intra-amniotic infection and low-level exposure to erythromycin were investigated. At 55 days of gestation twelve pregnant ewes received an intra-amniotic injection of a clinical U. parvum serovar 3 isolate, which was sensitive to macrolide antibiotics. At 100 days of gestation, ewes received standard maternal erythromycin treatment (30 mg/kg/day for four days, n = 6) or saline (n = 6). Preterm fetuses were surgically delivered at 125 days of gestation and ureaplasmas were cultured from the amniotic fluid and the chorioamnion. The minimum inhibitory concentrations (MICs) of erythromycin, azithromycin and roxithromycin were determined for cultured ureaplasma isolates, and antimicrobial susceptibilities were different between ureaplasmas isolated from the amniotic fluid (MIC range = 0.08 – 1.0 mg/L) and chorioamnion (MIC range = 0.06 – 5.33 mg/L). However, the increased resistance to macrolide antibiotics observed in chorioamnion ureaplasma isolates occurred independently of exposure to erythromycin in vivo. Remarkably, domain V of the 23S ribosomal RNA gene (which is the target site of macrolide antimicrobials) of chorioamnion ureaplasmas demonstrated significant variability (125 polymorphisms out of 422 sequenced nucleotides, 29.6%) when compared to the amniotic fluid ureaplasma isolates and the inoculum strain. This sequence variability did not occur as a consequence of exposure to erythromycin, as the nucleotide substitutions were identical between chorioamnion ureaplasmas isolated from different animals, including those that did not receive erythromycin treatment. We propose that these mosaic-like 23S ribosomal RNA gene sequences may represent gene fragments transferred via horizontal gene transfer. The significant differences observed in (i) susceptibility to macrolide antimicrobials and (ii) 23S ribosomal RNA sequences of ureaplasmas isolated from the amniotic fluid and chorioamnion suggests that the anatomical site from which they were isolated may exert selective pressures that alter the socio-microbiological structure of the bacterial population, by selecting for genetic changes and altered antimicrobial susceptibility profiles. The final experiment for this PhD examined antigenic size variation of the multiple banded antigen (MBA, a surface-exposed lipoprotein and predicted ureaplasmal virulence factor) in chronic, intra-amniotic ureaplasma infections. Previously defined ‘virulent-derived’ and ‘avirulent-derived’ clonal U. parvum serovar 6 isolates (each expressing a single MBA protein) were injected into the amniotic fluid of pregnant ewes (n = 20) at 55 days of gestation, and amniotic fluid was collected by amniocentesis every two weeks until the time of near-term delivery of the fetus (at 140 days of gestation). Both the avirulent and virulent clonal ureaplasma strains generated MBA size variants (ranging in size from 32 – 170 kDa) within the amniotic fluid of pregnant ewes. The mean number of MBA size variants produced within the amniotic fluid was not different between the virulent (mean = 4.2 MBA variants) and avirulent (mean = 4.6 MBA variants) ureaplasma strains (p = 0.87). Intra-amniotic infection with the virulent strain was significantly associated with the presence of meconium-stained amniotic fluid (p = 0.01), which is an indicator of fetal distress in utero. However, the severity of histological chorioamnionitis was not different between the avirulent and virulent groups. We demonstrated that ureaplasmas were able to persist within the amniotic fluid of pregnant sheep for 85 days, despite the host mounting an innate and adaptive immune response. Pro-inflammatory cytokines (interleukin (IL)-1â, IL-6 and IL-8) were elevated within the chorioamnion tissue of pregnant sheep from both the avirulent and virulent treatment groups, and this was significantly associated with the production of anti-ureaplasma IgG antibodies within maternal sera (p < 0.05). These findings suggested that the inability of the host immune response to eradicate ureaplasmas from the amniotic cavity may be due to continual size variation of MBA surface-exposed epitopes. Taken together, these data confirm that ureaplasmas are able to cause long-term in utero infections in a sheep model, despite standard antimicrobial treatment and the development of a host immune response. The overall findings of this PhD project suggest that ureaplasmas are able to cause chronic, intra-amniotic infections due to (i) the limited placental transfer of erythromycin, which prevents the accumulation of therapeutic concentrations within the amniotic fluid; (ii) the ability of ureaplasmas to undergo rapid selection and genetic variation in vivo, resulting in ureaplasma isolates with variable MICs to macrolide antimicrobials colonising the amniotic fluid and chorioamnion; and (iii) antigenic size variation of the MBA, which may prevent eradication of ureaplasmas by the host immune response and account for differences in neonatal outcomes. The outcomes of this program of study have improved our understanding of the biology and pathogenesis of this highly adapted microorganism.

Markers of chronic disease in offenders in a high secure correctional centre in Queensland

This study aimed to gauge the presence of markers of chronic disease, as a basis for food and nutrition policy in correctional facilities. One hundred and twenty offenders, recruited from a Queensland Correctional Centre, provided informed consent and completed both dietary interviews and physical measurements. Mean age of the sample was 35.5 ± 12 years (range = 19–77 yrs); mean age of the total population (n = 945) was 32.8 ± 10 years (range = 19–80 yrs). Seventy-nine participants also provided fasting blood samples. The mean body mass index (BMI) was 27 ± 3.5 kg/m2; 72% having a BMI > 25 kg/m2. Thirty-three percent were classified overweight or obese using waist circumference (mean = 92 ± 10 cm). Mean blood pressure measurement was systolic = 130 ± 14 mmHg and diastolic = 73 ± 10 mmHg. Twenty-four percent were classified as hypertensive of whom three were on antihypertensive medication. Eighteen percent had elevated triglycerides, and 40% unfavourable total cholesterol to HDL ratios. Homeostatic Model Assessment (HOMA scores) were calculated from glucose and insulin. Four participants were insulin resistant, two of whom had known diabetes. Metabolic syndrome, based on waist circumference (adjusted for ethnicity), blood lipids, blood pressure and plasma glucose indicated that 25% (n = 20) were classified with metabolic syndrome. Eighty-four percent (n = 120) reported some physical activity each day, with 51 percent participating ≥two times daily. Fifty-four percent reported smoking with an additional 20% having smoked in the past. Findings suggest that waist circumference rather than weight and BMI only should be used in this group to determine weight status. The data suggest that markers of chronic disease are present and that food and nutrition policy must reflect this. Further analysis is being completed to determine relevant policy initiatives.