Antiretroviral therapy (ART) adherence among people living with HIV/AIDS (PLHIV) in the north of Vietnam : a multi-method approach

The antiretroviral therapy (ART) program for People Living with HIV/AIDS (PLHIV) in Vietnam has been scaled up rapidly in recent years (from 50 clients in 2003 to almost 38,000 in 2009). ART success is highly dependent on the ability of the patients to fully adhere to the prescribed treatment regimen. Despite the remarkable extension of ART programs in Vietnam, HIV/AIDS program managers still have little reliable data on levels of ART adherence and factors that might promote or reduce adherence. Several previous studies in Vietnam estimated extremely high levels of ART adherence among their samples, although there are reasons to question the veracity of the conclusion that adherence is nearly perfect. Further, no study has quantitatively assessed the factors influencing ART adherence. In order to reduce these gaps, this study was designed to include several phases and used a multi-method approach to examine levels of ART non-adherence and its relationship to a range of demographic, clinical, social and psychological factors. The study began with an exploratory qualitative phase employing four focus group discussions and 30 in-depth interviews with PLHIV, peer educators, carers and health care providers (HCPs). Survey interviews were completed with 615 PLHIV in five rural and urban out-patient clinics in northern Vietnam using an Audio Computer Assisted Self-Interview (ACASI) and clinical records extraction. The survey instrument was carefully developed through a systematic procedure to ensure its reliability and validity. Cultural appropriateness was considered in the design and implementation of both the qualitative study and the cross sectional survey. The qualitative study uncovered several contrary perceptions between health care providers and HIV/AIDS patients regarding the true levels of ART adherence. Health care providers often stated that most of their patients closely adhered to their regimens, while PLHIV and their peers reported that “it is not easy” to do so. The quantitative survey findings supported the PLHIV and their peers’ point of view in the qualitative study, because non-adherence to ART was relatively common among the study sample. Using the ACASI technique, the estimated prevalence of onemonth non-adherence measured by the Visual Analogue Scale (VAS) was 24.9% and the prevalence of four-day not-on-time-adherence using the modified Adult AIDS Clinical Trials Group (AACTG) instrument was 29%. Observed agreement between the two measures was 84% and kappa coefficient was 0.60 (SE=0.04 and p<0.0001). The good agreement between the two measures in the current study is consistent with those found in previous research and provides evidence of cross-validation of the estimated adherence levels. The qualitative study was also valuable in suggesting important variables for the survey conceptual framework and instrument development. The survey confirmed significant correlations between two measures of ART adherence (i.e. dose adherence and time adherence) and many factors identified in the qualitative study, but failed to find evidence of significant correlations of some other factors and ART adherence. Non-adherence to ART was significantly associated with untreated depression, heavy alcohol use, illicit drug use, experiences with medication side-effects, chance health locus of control, low quality of information from HCPs, low satisfaction with received support and poor social connectedness. No multivariate association was observed between ART adherence and age, gender, education, duration of ART, the use of adherence aids, disclosure of ART, patients’ ability to initiate communication with HCPs or distance between clinic and patients’ residence. This is the largest study yet reported in Asia to examine non-adherence to ART and its possible determinants. The evidence strongly supports recent calls from other developing nations for HIV/AIDS services to provide screening, counseling and treatment for patients with depressive symptoms, heavy use of alcohol and substance use. Counseling should also address fatalistic beliefs about chance or luck determining health outcomes. The data suggest that adherence could be enhanced by regularly providing information on ART and assisting patients to maintain social connectedness with their family and the community. This study highlights the benefits of using a multi-method approach in examining complex barriers and facilitators of medication adherence. It also demonstrated the utility of the ACASI interview method to enhance open disclosure by people living with HIV/AIDS and thus, increase the veracity of self-reported data.

p53-independent NOXA induction overcomes apoptotic resistance of malignant melanomas

Once melanoma metastasizes, no effective treatment modalities prolong survival in most patients. This notorious refractoriness to therapy challenges investigators to identify agents that overcome melanoma resistance to apoptosis. Whereas many survival pathways contribute to the death-defying phenotype in melanoma, a defect in apoptotic machinery previously highlighted inactivation of Apaf-1, an apoptosome component engaged after mitochondrial damage. During studies involving Notch signaling in melanoma, we observed a gamma-secretase tripeptide inhibitor (GSI; z-Leu-Leu-Nle-CHO), selected from a group of compounds originally used in Alzheimer's disease, induced apoptosis in nine of nine melanoma lines. GSI only induced G2-M growth arrest (but not killing) in five of five normal melanocyte cultures tested. Effective killing of melanoma cells by GSI involved new protein synthesis and a mitochondrial-based pathway mediated by up-regulation of BH3-only members (Bim and NOXA). p53 activation was not necessary for up-regulation of NOXA in melanoma cells. Blocking GSI-induced NOXA using an antisense (but not control) oligonucleotide significantly reduced the apoptotic response. GSI also killed melanoma cell lines with low Apaf-1 levels. We conclude that GSI is highly effective in killing melanoma cells while sparing normal melanocytes. Direct enhancement of BH3-only proteins executes an apoptotic program overcoming resistance of this lethal tumor. Identification of a p53-independent apoptotic pathway in melanoma cells, including cells with low Apaf-1, bypasses an impediment to current cytotoxic therapy and provides new targets for future therapeutic trials involving chemoresistant tumors.

Determinants of skin self-examination (SSE) in men aged 50 years or older

Background: Queensland men aged 50 years and older are at high risk for melanoma. Early detection via skin self examination (SSE) (particularly whole-body SSE) followed by presentation to a doctor with suspicious lesions, may decrease morbidity and mortality from melanoma. Prevalence of whole-body SSE (wbSSE) is lower in Queensland older men compared to other population subgroups. With the exception of the present study no previous research has investigated the determinants of wbSSE in older men, or interventions to increase the behaviour in this population. Furthermore, although past SSE intervention studies for other populations have cited health behaviour models in the development of interventions, no study has tested these models in full. The Skin Awareness Study: A recent randomised trial, called the Skin Awareness Study, tested the impact of a video-delivered intervention compared to written materials alone on wbSSE in men aged 50 years or older (n=930). Men were recruited from the general population and interviewed over the telephone at baseline and 13 months. The proportion of men who reported wbSSE rose from 10% to 31% in the control group, and from 11% to 36% in the intervention group. Current research: The current research was a secondary analysis of data collected for the Skin Awareness Study. The objectives were as follows: • To describe how men who did not take up any SSE during the study period differed from those who did take up examining their skin. • To determine whether the intervention program was successful in affecting the constructs of the Health Belief Model it was aimed at (self-efficacy, perceived threat, and outcome expectations); and whether this in turn influenced wbSSE. • To determine whether the Health Action Process Approach (HAPA) was a better predictor of wbSSE behaviour compared to the Health Belief Model (HBM). Methods: For objective 1, men who did not report any past SSE at baseline (n=308) were categorised as having ‘taken up SSE’ (reported SSE at study end) or ‘resisted SSE’ (reported no SSE at study end). Bivariate logistic regression, followed by multivariable regression, investigated the association between participant characteristics measured at baseline and resisting SSE. For objective 2 proxy measures of self-efficacy, perceived threat, and outcome expectations were selected. To determine whether these mediated the effect of the intervention on the outcome, a mediator analysis was performed with all participants who completed interviews at both time points (n=830) following the Baron and Kenny approach, modified for use with structural equation modelling (SEM). For objective 3, control group participants only were included (n=410). Proxy measures of all HBM and HAPA constructs were selected and SEM was used to build up models and test the significance of each hypothesised pathway. A likelihood ratio test compared the HAPA to the HBM. Results: Amongst men who did not report any SSE at baseline, 27% did not take up any SSE by the end of the study. In multivariable analyses, resisting SSE was associated with having more freckly skin (p=0.027); being unsure about the statement ‘if I saw something suspicious on my skin, I’d go to the doctor straight away’ (p=0.028); not intending to perform SSE (p=0.015), having lower SSE self-efficacy (p<0.001), and having no recommendation for SSE from a doctor (p=0.002). In the mediator analysis none of the tested variables mediated the relationship between the intervention and wbSSE. In regards to health behaviour models, the HBM did not predict wbSSE well overall. Only the construct of self-efficacy was a significant predictor of future wbSSE (p=0.001), while neither perceived threat (p=0.584) nor outcome expectations (p=0.220) were. By contrast, when the HAPA constructs were added, all three HBM variables predicted intention to perform SSE, which in turn predicted future behaviour (p=0.015). The HAPA construct of volitional self-efficacy was also associated with wbSSE (p=0.046). The HAPA was a significantly better model compared to the HBM (p<0.001). Limitations: Items selected to measure HBM and HAPA model constructs for objectives 2 and 3 may not have accurately reflected each construct. Conclusions: This research added to the evidence base on how best to target interventions to older men; and on the appropriateness of particular health behaviour models to guide interventions. Findings indicate that to overcome resistance those men with more negative pre-existing attitudes to SSE (not intending to do it, lower initial self-efficacy) may need to be targeted with more intensive interventions in the future. Involving general practitioners in recommending SSE to their patients in this population, alongside disseminating an intervention, may increase its success. Comparison of the HBM and HAPA showed that while two of the three HBM variables examined did not directly predict future wbSSE, all three were associated with intention to self-examine skin. This suggests that in this population, intervening on these variables may increase intention to examine skin, but not necessarily the behaviour itself. Future interventions could potentially focus on increasing both the motivational variables of perceived threat and outcome expectations as well as a combination of both action and volitional self-efficacy; with the aim of increasing intention as well as its translation to taking up and maintaining regular wbSSE.

Postoperative low dose CT assessment of interbody fusion two years after thoracoscopic scoliosis surgery

The relationship between radiologic union and clinical outcomes in thoracoscopic scoliosis surgery is not clear, as apparent non-union of a spinal fusion does not always correspond to a poor clinical result. The aim of this study was to evaluate for the first time the interbody fusion rates using low dose CT scans at minimum 24 months after thoracoscopic scoliosis surgery, and to explore the relationship between fusion scores and; (i) rod diameter, (ii) graft type, (iii) fusion level, (iv) implant failure, and (v) lateral position in the disc space. The study found that moderate fusion scores on the Sucato scale secure successful clinical outcomes in thoracoscopic scoliosis surgery.

Neuroprotective effects of low-dose lithium in individuals at ultra-high risk for psychosis. A longitudinal MRI/MRS study

Objectives: To investigate if low-dose lithium may counteract the microstructural and metabolic brain changes proposed to occur in individuals at ultra-high risk (UHR) for psychosis. Methods: Hippocampal T2 relaxation time (HT2RT) and proton magnetic resonance spectroscopy (1H-MRS) measurements were performed prior to initiation and following three months of treatment in 11 UHR patients receiving low-dose lithium and 10 UHR patients receiving treatment as usual (TAU). HT2RT and 1H-MRS percentage change scores between scans were compared using one-way ANOVA and correlated with behavioural change scores. Results: Low-dose lithium significantly reduced HT2RT compared to TAU (p=0.018). No significant group by time effects were seen for any brain metabolites as measured with 1H-MRS, although myo-inositol, creatine, choline-containing compounds and NAA increased in the group receiving low-dose lithium and decreased or remained unchanged in subjects receiving TAU. Conclusions: This pilot study suggests that low-dose lithium may protect the microstructure of the hippocampus in UHR states as reflected by significantly decreasing HT2RT. Larger scale replication studies in UHR states using T2 relaxation time as a proxy for emerging brain pathology seem a feasible mean to test neuroprotective strategies such as low-dose lithium as potential treatments to delay or even prevent the progression to full-blown disorder.

Development of novel vaccine strategies to prevent genital tract chlamydial infections

Chlamydia trachomatis is the most prevalent bacterial sexually transmitted infection in the developed world and the leading cause of preventable blindness worldwide. As reported by the World Health Organization in 2001, there are approximately 92 million new infections detected annually, costing health systems billions of dollars to treat not only the acute infection, but also to treat infection-associated sequelae. The majority of genital infections are asymptomatic, with 50-70% going undetected. Genital tract infections can be easily treated with antibiotics when detected. Lack of treatment can lead to the development of pelvic inflammatory disease, ectopic pregnancies and tubal factor infertility in women and epididymitis and prostatitis in men. With infection rates on the continual rise and the large number of infections going undetected, there is a need to develop an efficacious vaccine which prevents not only infection, but also the development of infection-associated pathology. Before a vaccine can be developed and administered, the pathogenesis of chlamydial infections needs to be fully understood. This includes the kinetics of ascending infection and the effects of inoculating dose on ascension and development of pathology. The first aim in this study was to examine these factors in a murine model. Female BALB/c mice were infected intravaginally with varying doses of C. muridarum, the mouse variant of human C. trachomatis, and the ascension of infection along the reproductive tract and the time-course of infection-associated pathology development, including inflammatory cell infiltration, pyosalpinx and hydrosalpinx, were determined. It was found that while the inoculating dose did affect the rate and degree of infection, it did not affect any of the pathological parameters examined. This highlighted that the sexual transmission dose may have minimal effect on the development of reproductive sequelae. The results of the first section enabled further studies presented here to use an optimal inoculating dose that would ascend the reproductive tract and cause pathology development, so that vaccine efficacy could be determined. There has been a large amount of research into the development of an efficacious vaccine against genital tract chlamydial infections, with little success. However, there have been no studies examining the effects of the timing of vaccination, including the effects of vaccination during an active genital infection, or after clearance of a previous infection. These are important factors that need to be examined, as it is not yet known whether immunization will enhance not only the individual's immune response, but also pathology development. It is also unknown whether any enhancement of the immune responses will cause the Chlamydia to enter a dormant, persistent state, and possibly further enhance any pathology development. The second section of this study aimed to determine if vaccination during an active genital tract infection, or after clearance of a primary infection, enhanced the murine immune responses and whether any enhanced or reduced pathology occurred. Naïve, actively infected, or previously infected animals were immunized intranasally or transcutaneously with the adjuvants cholera toxin and CpG-ODN in combination with either the major outer membrane protein (MOMP) of C. muridarum, or MOMP and ribonucleotide reductase small chain protein (NrdB) of C. muridarum. It was found that the systemic immune responses in actively or previously infected mice were altered in comparison to animals immunized naïve with the same combinations, however mucosal antibodies were not enhanced. It was also found that there was no difference in pathology development between any of the groups. This suggests that immunization of individuals who may have an asymptomatic infection, or may have been previously exposed to a genital infection, may not benefit from vaccination in terms of enhanced immune responses against re-exposure. The final section of this study aimed to determine if the vaccination regimes mentioned above caused in vivo persistence of C. muridarum in the upper reproductive tracts of mice. As there has been no characterization of C. muridarum persistence in vitro, either ultrastructurally or via transcriptome analysis, this was the first aim of this section. Once it had been shown that C. muridarum could be induced into a persistent state, the gene transcriptional profiles of the selected persistent marker genes were used to determine if persistent infections were indeed present in the upper reproductive tracts of the mice. We found that intranasal immunization during an active infection induced persistent infections in the oviducts, but not the uterine horns, and that intranasal immunization after clearance of infection, caused persistent infections in both the uterine horns and the oviducts of the mice. This is a significant finding, not only because it is the first time that C. muridarum persistence has been characterized in vitro, but also due to the fact that there is minimal characterization of in vivo persistence of any chlamydial species. It is possible that the induction of persistent infections in the reproductive tract might enhance the development of pathology and thereby enhance the risk of infertility, factors that need to be prevented by vaccination, not enhanced. Overall, this study has shown that the inoculating dose does not affect pathology development in the female reproductive tract of infected mice, but does alter the degree and rate of ascending infection. It has also been shown that intranasal immunization during an active genital infection, or after clearance of one, induces persistent infections in the uterine horns and oviducts of mice. This suggests that potential vaccine candidates will need to have these factors closely examined before progressing to clinical trials. This is significant, because if the same situation occurs in humans, a vaccine administered to an asymptomatic, or previously exposed individual may not afford any extra protection and may in fact enhance the risk of development of infection-associated sequelae. This suggests that a vaccine may serve the community better if administered before the commencement of sexual activity.

Dose response relationships between physical activity, walking and health-related quality of life in mid-age and older women

Background Although physical activity is associated with health-related quality of life (HRQL), the nature of the dose-response relationship remains unclear. This study examined the concurrent and prospective dose-response relationships between total physical activity (TPA) and (only) walking with HRQL in two age cohorts of women. Methods Participants were 10,698 women born in 1946-1951 and 7,646 born in 1921-1926, who completed three mailed surveys for the Australian Longitudinal Study on Women's Health. They reported weekly TPA minutes (sum of walking, moderate, and vigorous minutes). HRQL was measured with the Medical Outcomes Study Short-Form 36 Health Status Survey (SF-36). Linear mixed models, adjusted for socio-demographic and health-related variables, were used to examine associations between TPA level (none, very low, low, intermediate, sufficient, high, and very high) and SF-36 scores. For women who reported walking as their only physical activity, associations between walking and SF-36 scores were also examined. Results Curvilinear trends were observed between TPA and walking with SF-36 scores. Concurrently, HRQL scores increased significantly with increasing TPA and walking, in both cohorts, with increases less marked above sufficient activity levels. Prospectively, associations were attenuated although significant and meaningful improvements in physical functioning and vitality were observed across most TPA and walking categories above the low category. Conclusion For women in their 50s-80s without clinical depression, greater amounts of TPA are associated with better current and future HRQL, particularly physical functioning and vitality. Even if walking is their only activity, women, particularly those in their 70s-80s, have better health-related quality of life.

Computer planning of stereotactic iodine-125 seed brachytherapy for recurrent malignant gliomas

At St Thomas' Hospital, we have developed a computer program on a Titan graphics supercomputer to plan the stereotactic implantation of iodine-125 seeds for the palliative treatment of recurrent malignant gliomas. Use of the Gill-Thomas-Cosman relocatable frame allows planning and surgery to be carried out at different hospitals on different days. Stereotactic computed tomography (CT) and positron emission tomography (PET) scans are performed and the images transferred to the planning computer. The head, tumour and frame fiducials are outlined on the relevant images, and a three-dimensional model generated. Structures which could interfere with the surgery or radiotherapy, such as major vessels, shunt tubing etc., can also be outlined and included in the display. Catheter target and entry points are set using a three-dimensional cursor controlled by a set of dials attached to the computer. The program calculates and displays the radiation dose distribution within the target volume for various catheter and seed arrangements. The CT co-ordinates of the fiducial rods are used to convert catheter co-ordinates from CT space to frame space and to calculate the catheter insertion angles and depths. The surgically implanted catheters are after-loaded the next day and the seeds left in place for between 4 and 6 days, giving a nominal dose of 50 Gy to the edge of the target volume. 25 patients have been treated so far.

Insights to the Clarification of Sugar Cane Juice Expressed from Sugar Cane Stalk and Trash

Processing of juice expressed from green sugar cane containing all the trash (i.e., tops and leaves, the nonstalk component) of the sugar cane plant during sugar manufacture has been reported to lead to poor clarified juice (CJ) quality. Studies of different liming techniques have been conducted to identify which liming technique gives the best clarification performance from juice expressed from green cane containing half of all trash extracted (GE). Results have shown that lime saccharate addition to juice at 76 °C either continuous or batchwise gives satisfactory settling rates of calcium phosphate flocs(50−70 cm/min) and CJ with low turbidity and minimal amounts of mineral constituents. Surprisingly, the addition of phosphoric acid (≤300 mg/kg as P2O5), prior to liming to reduce juice turbidity (≤80%), increased the Mg (≤101%) and Si(≤148%) contents particularly for clarified GE juices. The increase was not proportional with increasing phosphoric acid dose. The nature of the flocs formed, including the zeta potential of the particles by the different liming techniques, has been used to account for the differences in clarification performance. Differences between the qualities of the CJ obtained with GE juice and that of burnt cane juices with all trash extracted (BE) have been discussed to provide further insights into GE processing.

Towards determining soft tissue properties for modelling spine surgery : current progress and challenges

Current complication rates for adolescent scoliosis surgery necessitate the development of better surgical planning tools to improve outcomes. Here we present our approach to developing finite element models of the thoracolumbar spine for deformity surgery simulation, with patient-specific model anatomy based on low-dose pre-operative computed tomography scans. In a first step towards defining patient-specific tissue properties, an initial 'benchmark' set of properties were used to simulate a clinically performed pre-operative spinal flexibility assessment, the fulcrum bending radiograph. Clinical data for ten patients were compared with the simulated results for this assessment and in cases where these data differed by more than 10%, soft tissue properties for the costo-vertebral joint (CVJt) were altered to achieve better agreement. Results from these analyses showed that changing the CVJt stiffness resulted in acceptable agreement between clinical and simulated flexibility in two of the six cases. In light of these results and those of our previous studies in this area, it is suggested that spinal flexibility in the fulcrum bending test is not governed by any single soft tissue structure acting in isolation. More detailed biomechanical characterisation of the fulcrum bending test is required to provide better data for determination of patient-specific soft tissue properties.