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Given its potential antiviral activity, we investigated the effect of teriflunomide on EBV in patients with relapsing-remitting MS (RRMS).Saliva samples were collected at home and analysed for EBV DNA presence in patients with RRMS treated with teriflunomide for ≥3 months.The proportion of patients with detectable EBV in the teriflunomide cohort was lower than in the reference cohorts. The proportion of samples with EBV DNA or shedding from teriflunomide-treated patients was reduced relative to each reference cohort (P0.0001;5.8 virus copies/µL cut-off).This pilot study demonstrated the feasibility of at-home saliva sample collection and revealed a possible effect of teriflunomide on EBV shedding.

Background The exponential growth in the reach and development of new technologies over the past decade means that mobile technologies and social media play an increasingly important role in service delivery models to maximise HIV testing and access to treatment and care. This systematic review examines the impact of electronic and mobile technologies in medical care (eHealth) in the linkage to and retention of priority populations in the HIV treatment and care cascade, focussing on the Asia-Pacific region. Methods The review was informed by the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement from the Cochrane Collaboration guidelines. Both grey and published scientific literature from five different databases were searched for all original articles in English published from 2010 to 2017. Studies conducted outside the Asia-Pacific region or not including HIV priority populations were excluded. The methodological quality of studies included in the review was assessed using the Quality Assessment Tool for Quantitative Studies. Results The database search identified 7309 records. Of the 224 peer-reviewed articles identified for full text review, 16 studies from seven countries met inclusion criteria. Six cross sectional studies found evidence to support the use of eHealth, via text messages, instant messaging, social media and health promotion websites, to increase rates of HIV testing and re-testing among men who have sex with men (MSM). Evidence regarding the efficacy of eHealth interventions to improve antiretroviral treatment (ART) adherence was mixed, where one randomised controlled trial (RCT) showed significant benefit of weekly phone call reminders on improving ART adherence. Three further RCTs found that biofeedback eHealth interventions that provided estimated ART plasma concentration levels, showed promising results for ART adherence. Conclusions This review found encouraging evidence about how eHealth can be used across the HIV treatment and care cascade in the Asia-Pacific region, including increasing HIV testing and re-testing in priority populations as well as ART adherence. eHealth interventions have an important role to play in the movement towards the end of AIDS, particularly to target harder-to-reach HIV priority populations, such as MSM. Electronic supplementary material The online version of this article (10.1186/s12879-018-2972-5) contains supplementary material, which is available to authorized users.

Background: Neuroinflammation and human endogenous retroviruses (HERV-K) are thought to have a role in the pathophysiology of amyotrophic lateral sclerosis (ALS). Therapy directed against endogenous retroviruses has demonstrated positive effects during in-vitro and biomarker studies. Consequently, the present study was undertaken to assess the safety and tolerability of long-term Triumeq (abacavir, lamivudine and dolutegravir) exposure in patients with ALS and to assess efficacy against biomarkers of disease progression. Methods: Patients were observed during a 10-week lead-in period before receiving Triumeq treatment for 24 weeks at four specialist ALS centres. The primary outcomes were safety and tolerability. Secondary outcomes included HERV-K expression levels, urinary p75ECD levels, neurophysiological parameters and clinical outcomes. The ENCALS prediction model was applied to provide an estimate of the cohort survival. The trial was registered on www.clinicaltrials.gov (NCT02868580). Findings: 40 patients with ALS received Triumeq and 35 (88%) completed treatment. There were no drug-related serious adverse events; one patient was withdrawn from the study due to a drug-associated increase in liver enzymes. A favourable response on HERV-K expression levels was observed, accompanied by a potential slowing in ALSFRS-R progression rate of 21.8% (95% CI -4.8 %- 48.6%) and the amount of urinary p75ECD measured. One patient died five months after stopping treatment, while five were expected to have died during the treatment period (interquartile range 2-8). Interpretation: Long-term Triumeq exposure was safe and well tolerated. There was suggestive evidence for a biological response in pharmacodynamic and clinical biomarkers. A larger international phase III trial will be deployed to assess the effect of Triumeq on overall survival and disease progression. Funding: Funding was provided by the FightMND Foundation; MND Research Institute of Australia; MND Association, United Kingdom. ViiV Healthcare provided the Triumeq. Declaration of Interest: The authors have no conflict of interest with respect to the research or data presented in this study. No funder was involved in the study design or interpretation or reporting of the results. Ethical Approval: The relevant ethics committees at each site approved the protocol. The study was conducted in accordance with Good Clinical Practice (GCP) and the Declaration of Helsinki (2000). The trial was registered on clinicaltrials.gov (NCT02868580).

Reactivation of Human Endogenous Retrovirus K (HERV-K), subtype HML-2, has been associated with pathophysiology of amyotrophic lateral sclerosis (ALS). We aimed to assess the efficacy of antiretroviral therapy in inhibiting HML-2 in patients with ALS and a possible association between the change in HML-2 levels and clinical outcomes. We studied the effect of 24-weeks antiretroviral combination therapy with abacavir, lamivudine, and dolutegravir on HML-2 levels in 29 ALS patients. HML-2 levels decreased progressively over 24 weeks (P = 0.001) and rebounded within a week of stopping medications (P = 0.02). The majority of participants (82%), defined as “responders”, experienced a decrease in HML-2 at week 24 of treatment compared to the pre-treatment levels. Differences in the evolution of some of the clinical outcomes could be seen between responders and non-responders: FVC decreased 23.69% (SE = 11.34) in non-responders and 12.71% (SE = 8.28) in responders. NPI score decreased 91.95% (SE = 6.32) in non-responders and 53.05% (SE = 10.06) in responders (P = 0.01). Thus, participants with a virological response to treatment showed a trend for slower progression of the illness. These findings further support the possible involvement of HML-2 in the clinical course of the disease.

Background\ud Epstein Barr Virus (EBV) infection is closely associated with multiple sclerosis (MS), but the relationship between viral load and disease activity is unclear. This study tested the observed levels of salivary EBV in MS, as a first step in investigating this relationship.\ud \ud Methods\ud Real-time quantitative PCR (qPCR) was used to measure EBV DNA levels in saliva samples from three separate Multiple Sclerosis (MS) patient cohorts.\ud \ud Results\ud The qPCR assay was used to delineate EBV shedding, defined here as a reliably detectable level of extracellular EBV DNA in saliva. Frequency of EBV shedding was found to be similar across the groups, with 20-25% of subjects releasing virus on any given sampling date.\ud \ud Diurnal variation in EBV count was tested in one of the cohorts, in which 26% of subjects showed more than a 10-fold difference between the highest and lowest EBV levels on a single day. In the same cohort, elevated viral levels at one time point did not predict elevated viral levels at a subsequent time point.\ud \ud Conclusions\ud These results indicate that EBV lytic activity in a subject cannot be inferred from a single measure of EBV in saliva. Also, subjects do not appear to be behave constantly as “EBV shedders” or “non-shedders”. The assay is useful in giving a clear indication of salivary gland EBV lytic activity across a patient cohort – for example, in testing anti-viral drugs in MS.

The causes of multiple sclerosis and amyotrophic lateral sclerosis have long remained elusive. A new category of pathogenic components, normally dormant within human genomes, has been identified: human endogenous retroviruses (HERVs). These represent ∼8% of the human genome, and environmental factors have reproducibly been shown to trigger their expression. The resulting production of envelope (Env) proteins from HERV-W and HERV-K appears to engage pathophysiological pathways leading to the pathognomonic features of MS and ALS, respectively. Pathogenic HERV elements may thus provide a missing link in understanding these complex diseases. Moreover, their neutralization may represent a promising strategy to establish novel and more powerful therapeutic approaches., Highlights HERVs, retroviral sequences integrated into the genome during evolution, are now known to represent 8% of the human genome. These were recently shown to comprise copies that retain potential to express retroviral proteins or particles, and can be abnormally expressed in autoimmune, neurodegenerative, chronic inflammatory diseases, and cancer. Environmental factors such as specific viral infections were shown to potently activate HERVs under tissue-specific and temporal conditions. Of several diseases in which abnormal activation and expression of HERV proteins have been reported, studies over recent decades have led to a proof of concept that HERVs play a key role in the pathogenesis of MS and ALS. HERV-W and HERV-K Env proteins induce pathogenic effects in vitro and in vivo that are relevant to the pathognomonic features of these diseases. These endogenous retroviruses are potential novel therapeutic targets that are now being addressed with innovative therapeutic strategies in clinical trials.

We study the isoperimetric subgraphs of the giant component $\textbf{C}_n$ of supercritical bond percolation on the square lattice. These are subgraphs of $\textbf{C}_n$ having minimal edge boundary to volume ratio. In contrast to the work of Biskup, Louidor, Procaccia and Rosenthal, the edge boundary is taken only within $\textbf{C}_n$ instead of the full infinite cluster. The isoperimetric subgraphs are shown to converge almost surely, after rescaling, to the collection of optimizers of a continuum isoperimetric problem emerging naturally from the model. We also show that the Cheeger constant of $\textbf{C}_n$ scales to a deterministic constant, which is itself an isoperimetric ratio, settling a conjecture of Benjamini in dimension two., 42 pages, 8 figures, comments welcome

Background Although the aetiology of multiple sclerosis (MS) remains elusive, it is clear that Epstein Barr virus (EBV) and possibly other viruses play a role in the pathogenesis of MS. Laboratory evidence suggests that human endogenous retroviruses (HERVs) could also have a role, but no interventional therapy has determined what will happen if HERVs are suppressed. Recent epidemiological evidence indicates patients with HIV infection have a significantly lower risk of developing MS and that HIV antiretroviral therapies may be coincidentally inhibiting HERVs, or other retroelements, that could be implicated in MS. Objectives To systematically investigate the effects of an HIV integrase strand inhibitor, raltegravir, on the number of gadolinium (Gd)-enhanced MRI lesions in people with active relapsing MS. Methods This is a Phase 2a clinical trial where twenty participants were enrolled in a 3 month baseline phase followed by 3 months of treatment with raltegravir 400 mg twice a day. Patients had monthly Gd-enhanced MRI, saliva collection to test for EBV shedding, blood sampling for safety monitoring, virology (including HERVs), measurement of immunological and inflammatory markers; and physical, neurological and quality-of-life assessments. Results All patients completed the six months trial period.The primary outcome measure of MS disease activity was the number of Gd-enhancing lesions observed, and raltegravir had no significant effect on the rate of development of Gd-enhancing lesions during the treatment phase compared with the baseline phase. Additionally, there was no change in secondary outcomes of either disability or quality-of-life measures that could reasonably be attributed to the intervention. There was a significant positive between HERV-W/MSRV (multiple sclerosis related virus) Gag Flix (Fluorescence index) B cells and the number of Gd-enhanced lesions at any visit (p = 0.029), which was independent of any potential influence of the trial drug administration. Regarding EBV shedding, there was no significant correlation between the amount of EBV shedding and the number of lesions. No change was detected in inflammatory markers (IL-8, IL-1β, IL-6, IL-10, TNF, IL-12p70 and HCRP), which were all within normal limits both before and after the intervention. Serum CD163 expression was also unchanged by raltegravir. Conclusions Raltegravir did not have any impact on MS disease activity. This could be due to the choice of antiretroviral agent used in this study, the need for a combination of agents, as used in treating HIV infection, the short treatment period or dosing regimen, or the lack of a role of HERV expression in MS once the disease is established. Borderline significance for the association between EBV shedding and the total number of lesions, probably driven by new lesion development, may indicate EBV shedding as a marker of inflammatory disease activity. In conclusion, interesting correlations between HERV-W markers, EBV shedding and new MRI lesions, independent from treatment effects, were found.

We consider a continuous time random walk on the two-dimensional discrete torus, whose motion is governed by the discrete Gaussian free field on the corresponding box acting as a potential. More precisely, at any vertex the walk waits an exponentially distributed time with mean given by the exponential of the field and then jumps to one of its neighbors, chosen uniformly at random. We prove that throughout the low-temperature regime and at in-equilibrium timescales, the process admits a scaling limit as a spatial K-process driven by a random trapping landscape, which is explicitly related to the limiting extremal process of the field. Alternatively, the limiting process is a supercritical Liouville Brownian motion with respect to the continuum Gaussian free field on the box. This demonstrates rigorously and for the first time, as far as we know, a dynamical freezing in a spin glass system with logarithmically correlated energy levels., Final version available at Electron. J. Probab

The Second International Workshop on Human Endogenous Retroviruses and Disease, Washington DC, March 13-14 2017 brought together international basic and clinical scientists investigating the involvement of human endogenous retroviruses (HERVs) in complex human diseases.

Objectives: Even though multiple sclerosis (MS) and HIV infection are well-documented conditions in clinical medicine, there is only a single case report of a patient with MS and HIV treated with HIV antiretroviral therapies. In this report, the patient' s MS symptoms resolved completely after starting combination antiretroviral therapy and remain subsided for more than 12 years. Authors hypothesised that because the pathogenesis of MS has been linked to human endogenous retroviruses, antiretroviral therapy for HIV may be coincidentally treating or preventing progression of MS. This led researchers from Denmark to conduct an epidemiological study on the incidence of MS in a newly diagnosed HIV population (5018 HIV cases compared with 50 149 controls followed for 31 875 and 393 871 person-years, respectively). The incidence rate ratio for an HIV patient acquiring MS was low at 0.3 (95% CI 0.04 to 2.20) but did not reach statistical significance possibly due to the relatively small numbers in both groups. Our study was designed to further investigate the possible association between HIV and MS. Methods: We conducted a comparative cohort study accessing one of the world's largest linked medical data sets with a cohort of 21 207 HIV-positive patients and 5 298 496 controls stratified by age, sex, year of first hospital admission, region of residence and socioeconomic status and 'followed up' by record linkage. Results: Overall, the rate ratio of developing MS in people with HIV, relative to those without HIV, was 0.38 (95% CI 0.15 to 0.79). Conclusions: HIV infection is associated with a significantly decreased risk of developing MS. Mechanisms of this observed possibly protective association may include immunosuppression induced by chronic HIV infection and antiretroviral medications.

We study the isoperimetric subgraphs of the infinite cluster $\textbf{C}_\infty$ for supercritical bond percolation on $\mathbb{Z}^d$ with $d\geq 3$. Specifically, we consider the subgraphs of $\textbf{C}_\infty \cap [-n,n]^d$ which have minimal open edge boundary to volume ratio. We prove a shape theorem for these subgraphs, obtaining that when suitably rescaled, these subgraphs converge almost surely to a translate of a deterministic shape. This deterministic shape is itself an isoperimetric set for a norm we construct. As a corollary, we obtain sharp asymptotics on a natural modification of the Cheeger constant for $\textbf{C}_\infty \cap [-n,n]^d$. This settles a conjecture of Benjamini for the version of the Cheeger constant defined here., 73 pages, exposition greatly improved, to appear Ann. Inst. H. Poincar\'{e} Probab. Statist

In 2006 the avian influenza A (H5N1) virus received considerable media coverage in Australia, as it did in many other countries. It is often argued that the media sensationalizes health crises, and experts cautioned about the risk of panic as a result of fear of avian influenza. The purpose of the present study was to systematically analyze Australian print media coverage of avian influenza in 2006 and to examine whether this coverage served the purpose of informing, rather than alarming, the general public. For the period January 1, 2006 to December 31, 2006, 20 Australian newspaper titles were monitored for coverage of avian influenza. The identified articles were analyzed using aspects of protection motivation theory for theoretical direction to determine whether there were any consistent themes or perspectives in the coverage. A total of 850 articles were identified for analysis. Concerning vulnerability, 46% of articles reported the incidence of human cases, with 24% noting that avian influenza was a potential threat to Australia. The most common severity theme was “deadly” with over 50% of mentions, followed by “pandemic” with 35%. Only 11% of articles referred to any form of self-protection. We found that a considerable proportion of the articles reporting on avian influenza were framed in a way that had the potential to incite fear and panic amongst the public; the intensity of media coverage reduced over time; and, of particular concern, that there was little media coverage that focused on protective or preventative issues. Whether an influenza pandemic eventuates or not, it is prudent for governments and health authorities to continually develop appropriate resources and strategies to prepare the health system and the general public to respond to current, and future, infectious disease risks.

It is widely accepted that changes in sexual behaviour in the mid-1980s drastically reduced the spread of human immunodeficiency virus (HIV) through male homosexual contact in Western countries, but documentation of changes in infection rates has been based on observation of subjects enrolled in cohort studies, who may be highly selected and motivated. In this study, the incidence of HIV seroconversion was investigated among people attending a major site of HIV testing, counselling and patient care in Sydney. Over the period March 1985 to June 1990, 2 301 people were tested for HIV antibody on more than one occasion, following a negative result at the first test. On the basis of subsequent tests, 107 were found to have seroconverted during the study period, including 91 men who reported homosexual or bisexual contact as their only exposure to HIV. Overall, the incidence rate of HIV infection among men reporting homosexual or bisexual contact was 404 per 100 person-years of follow-up. Under various methods of calculation, the incidence was estimated to have declined between 1985 and 1989–1990. However, there was continuing HIV seroconversion in 1989–1990 and no indication of declining incidence in younger men. The fall in HIV incidence documented in this study supports the role of HIV prevention programs aimed at homosexual and bisexual men.

Introduction: The speed with which Thailand has scaled up public provision of antiretroviral therapy (ART) has been unprecedented, with more than 80000 individuals on treatment at the end of 2006 through Thailand's National Access to Antiretroviral Program for People Living with HIV/AIDS (NAPHA). This paper projects the cost effectiveness, the affordability and the future fiscal burden of NAPHA to the government of Thailand under several different policy scenarios until the year 2025. Methods: An economic/epidemiological model of access to ART was constructed, and this composite model was calibrated to economic and epidemiological data from Thailand and other countries. The economic model adopts the conditional logit specification of demand allocation across multiple treatment modes, and the epidemiological model is a deterministic difference-equation model fitted to the cumulated data on HIV incidence in each risk group. Results: The paper estimates that under 2005 prices NAPHA will save life-years at approximately US$736 per life-year saved with first-line drugs alone and for approximately US$2145 per life-year if second-line drugs are included. Enhancing NAPHA with policies to recruit patients soon after they are first eligible for ART or to enhance their adherence would raise the cost per life-year saved, but the cost would be small per additional life-year saved, and is therefore justifiable. The fiscal burden of a policy including second as well as first-line drugs would be substantial, rising to 23% of the total health budget by 2014, but the authors judge this cost to be affordable given Thailand's strong overall economic performance. The paper estimates that a 90% reduction in the future cost of second-line therapy by the exercise of Thailand's World Trade Organization authority to issue compulsory licences would save the government approximately US$3.2 billion to 2025 and reduce the cost of NAPHA per life-year saved from US$2145 to approximately US$940.

In recent times the world has faced several potential pandemics – SARS, avian (bird) flu, swine flu, and most recently Ebola. The risk of a disease pandemic presents an important challenge for social marketing –to this point, health-related social marketing has focused on chronic diseases (such as cancer, asthma, obesity) and their risk factors (such as tobacco use, physical inactivity, and dietary intake). In the communicable disease field, most of the challenges we have addressed have had simple and proven preventive strategies (such as immunisation and the use of condoms). However, emerging pandemic diseases pose new challenges – notably in the global scale of the threat, the rapid nature of transmission, and (often) the absence of a known cure or vaccine. In this context, people’s quality of life has scope to be shaped by immense physical and social influences. This chapter reports on a comprehensive study undertaken to inform government policy and practice in the event of an avian influenza pandemic – specifically how to prepare (but not panic) the general public. The research phases included: a media analysis of coverage of a potential pandemic; extensive qualitative formative research; two population CATI surveys; two airport intercept surveys; message development; and message testing. While this research was undertaken in the context of a specific disease, the findings and recommendations are equally relevant to current and future pandemic threats.

Heat shock protein (HSP) expression in lymphocytes isolated from 20 patients with HIV disease and 15 age-matched controls was determined. Fold increases in lymphocyte hsp70 expression after heat shock were 4.52 +/- 2.97 in HIV-positive individuals compared with 2.60 +/- 1.29 for HIV-negative controls (P= 0.001). Given clear roles for HSP in the cross-presentation of antigens, alpha-defensin internalization and pro-inflammatory cytokine production, a further investigation of HSP in HIV patients is merited.

Objective: To investigate the effect of antioxidant supplementation on viral load and the antioxidant/reactive oxygen species system in people with HIV. Design: Single centre, prospective, dose comparison study. Setting: Outpatient clinic specializing in HIV care. Subjects: Sixty-six participants were sequentially recruited by advertisement, and 48 subjects completed the study. Interventions: A recommended dose antioxidant regimen (5450 IU vitamin A as β-carotene, 250 mg vitamin C, 100 IU vitamin E, 100 µg selenium, 50 mg coenzyme Q10) or a high-dose antioxidant regimen (21 800 IU vitamin A as β-carotene, 1000 mg vitamin C, 400 IU vitamin E, 200 µg selenium, 200 mg coenzyme Q10) for a 12 week period. Results: Using repeated measures analysis of variance, the changes over treatment time were significant for selenium, glutathione, glutathione peroxidase and lipid peroxides (P 0.05). The main effects for group and the interaction effects were not significant for any of the parameters measured (P≥0.05). Conclusion: Antioxidant supplementation significantly improved some measures of oxidative defence. There was no benefit in using a high-dose supplement in this study. Sponsorship: Blackmores Ltd supplied the antioxidant supplements. European Journal of Clinical Nutrition (2001) 55, 107–114

Objectives: To identify risk factors for non-Hodgkin's lymphoma (NHL) in people with HIV infection. Design and setting: Case-control study in Sydney, Australia. Participants and methods: Two hundred and nineteen patients with AIDS-related NHL were compared with 219 HIV-infected controls without NHL, matched for CD4 positive cell count and date of specimen collection. Data on demographic, infectious, treatment-related and immunological factors were abstracted by medical record review. The association between demographic factors, sexually transmissible diseases, HIV-related opportunistic infections, anti-viral therapy, duration of immune deficiency and indices of immune stimulation and risk of NHL were derived for these groups. Results: In a multivariate model, there were two independent groups of predictors of NH risk. The first was duration of immunodeficiency, as measured by longer time since seroconversion (P for trend 0.008), and lower CD4 positive cell count 1 year prior to the time of NHL diagnosis (P for trend 0.009). The second predictor was B-cell stimulation, as indicated by higher serum globulin (a surrogate marker for serum immunoglobulin, Pfor trend 0.044) and HIV p24 antigenaemia [odds ratio (OR) for p24 positivity, 1.82; 95% confidence interval (CI), 1.15-2.88]. Indices of B-cell stimulation preceded the diagnosis of NHL by several years. Factors not related to NHL risk included clinical indices of Epstein-Barr virus infection and receipt of individual nucleoside analogue antiretroviral agents. Combination therapy with these agents was associated with a non-significant reduction in NHL risk (OR, 0.68; 95% CI, 0.39-1.18). Conclusions: Markers of long-standing immune deficiency and B-cell stimulation were associated with an increased risk of developing NHL. Unless the strongest risk factor for NHL, immune deficiency, can be reversed, NHL is likely to become proportionately more important as a cause of morbidity and mortality in people with HIV infection.

Objective The authors prospectively studied visual outcome, relapse, complications, and survival of patients with acquired immune deficiency syndrome (AIDS)-related cytomegalovirus (CMV) treated with high-dose intravitreous ganciclovir (2 mg/0.1 ml) injections. The outcomes were compared with those of patients treated with standard doses of intravenous ganciclovir in the same institution. The histopathologic and electrophysiologic effects of high-dose intravitreous ganciclovir injections in rabbits also were studied. Design A nonrandomized case series. Participants A total of 42 patients (74 eyes) were treated with intravitreous injections and 18 patients (27 eyes) were treated with intravenous ganciclovir. Five eyes of three New Zealand white rabbits were injected with ganciclovir, and the sixth eye was a control specimen. Intervention Patients treated with intravitreous injections received twice-weekly doses of 2 mg/0.1 ml ganciclovir for 3 weeks, then weekly injections. Patients treated with intravenous ganciclovir received standard doses. Patients were monitored with regular examinations. Rabbit eyes were given intravitreous injections of 1 mg/0.1 ml of ganciclovir weekly for 4 weeks. Main outcome measures Assessments of vision, retinal inflammation, and survival were made. Electroretinograms were performed on the rabbit eyes, and they were processed for light and electron microscopy. Results In the intravitreous group, visual acuity (VA) was stable in 64 of 74 eyes, 5 improved, and 5 deteriorated. Sixty-three (85%) of 74 eyes had final VA of 20/20 to 20/40. Relapse occurred in five eyes (7%; median time, 42 weeks). There were three cases of endophthalmitis. Median survival after diagnosis of CMV retinitis was 36 weeks. In the intravenous group, VA was stable in 18 eyes, 0 improved, and 9 deteriorated. Sixteen (59%) of 27 eyes had final VA of 20/20 to 20/40. Relapse occurred in 15 eyes (56%) at a median time of 21 weeks. Median survival was 21 weeks. The rabbit studies showed no evidence of toxicity. Conclusion High-dose intravitreous ganciclovir effectively suppressed CMV retinitis, preserved vision, and prevented relapse without deterioration in survival.

We report the referral of an HIV-infected surgeon and a subsequent first-ever recommended look-back investigation in Hong Kong. Efficient coordination and effective implementation of the look-back investigation yielded a high response rate of 92.3% of priority patients, with none tested HIV positive. Our experience reconfirmed the very small risk of provider-to-patient HIV transmission and the crucial importance of infection control.

Population-based acquired immune deficiency syndrome (AIDS) incidence in Australia in 1991-1993 was ascertained. The National Centre in HIV Epidemiology and Clinical Research obtained information on AIDS cases from notification by doctors of AIDS diagnoses through the Department of Health in each state and territory. Information on the Australian population, broken down by sex, age group, country of birth and geographic area of residence was obtained from the Australian Bureau of Statistics. To the end of February 1995, 2341 cases of AIDS were reported as having been diagnosed in Australia during 1991-1993. Of these, 96 per cent were in males, of whom over 72 per cent were in the age group 25-44 years. Geographic concentration of AIDS cases was observed: over 55 per cent of cases were in New South Wales (NSW) and these were concentrated in inner Sydney, in particular, in two metropolitan health areas: Eastern Sydney and Central Sydney. Age-standardised average annual incidence per 100,000 population was 8.9 for males, 0.4 for females and 4.6 overall. This incidence varied widely when the population was subdivided by Local Government Area, especially in NSW, where incidence for males varied from 0.0 to 204.4. The highest average annual incidence per 100,000 population by country of birth was recorded for people born in North America, which was almost four times higher than that for people born in Australia. Although AIDS cases diagnosed in 1991-1993 were concentrated on the metropolitan area of capital cities, cases also occurred in rural areas.

To evaluate the safety and efficacy of the anabolic steroid, nandrolone decanoate (Deca Durabolin) in patients with HIV wasting who are resistant to nutritional intervention.A 16-week open trial with subjects who had lost 5-15% of their usual body weight.HIV/AIDS specialist ambulatory care services, both public and private, in sydney, Australia.Two hundred and twenty men entered the pre-therapy phase, and of these, 24 failed to gain weight and were enrolled. Seventeen subjects (81%) completed the 16-week trial.Pre-therapy nutritional assessment and education was conducted by the clinical dietitian. Those who failed to gain weight (10.9%) were treated with nandrolone decanoate (100 mg/ml) by deep intramuscular injection every 2 weeks for 16 weeks.Changes in weight and body composition (lean body mass, total body water and nitrogen index) were measured by anthropometry, bioelectrical impedance, and in vivo neutron activation. Changes in quality of life were assessed by the 30-item Medical Outcomes Study short form questionnaire. Changes in biochemistry, haematology and immunology were also measured.There were significant increases in weight (mean, 0.14 kg per week; P0.05) and lean body mass (mean, 3 kg by anthropometry; P0.005). The change in lean body mass was of similar magnitude across all measurement modalities. Quality of life parameters, especially functionality, increased significantly during the trial. No subject experienced toxicity.Nandrolone decanoate has beneficial effects on weight, lean body mass and quality of life in selected patients who have mild to moderate HIV wasting.

In Part I of this five part series, we introduced the fundamentally important concept of validity of data. In Part II, studydesign and the principles of causality will be explored

Two consecutive samples one year apart of injecting drug users ( n=754 and n=345) were collected in Sydney, Australia and analysed for predictors of Human Immunodeficiency Virus (HIV) prevalence. Data indicated that similar variables were associated with HIV infection in both waves of the study. Risks for HIV infection included number of injections in last typical using month, acceptance of used injecting equipment from other injecting drug users (IDUs) who were known to be infected either before or after the sharing occurred, having sex with people known to be infected with HIV, and sexual orientation. It was not possible to determine whether sexual or equipment sharing with known HIV infected people preceded or followed HIV infection. These data confirm that predictors of HIV prevalence in Sydney are similar to those found in overseas studies and that sexual orientation appears to be the most powerful predictor. These data suggest both that sexual contact is an important route of infection in IDUs, and that sexual risks for HIV infection in IDUs need to be emphasised.

We examined the explanations given by a sample of 1245 injecting drug users in Sydney, Australia for accepting used injection equipment. Factor analysis of these reasons revealed three dimensions of sharing: not caring when withdrawing or intoxicated, unavailability of equipment, and not seeing it as high risk or ease of injecting. The most common reasons given were difficulty in obtaining sterile equipment (73% of cases), the dangers not seeming so important when in withdrawal (40%) and sharing being something done with friends or lovers (31%). Most common reasons for not sharing were related to health issues (91% citing AIDS and 67% hepatitis). These data suggest that interventions target provision of sterile equipment, and education which highlights risk situations such as intoxication and withdrawal.

Transmission of HIV by sexual contact as well as through sharing of contaminated injection equipment is a source of viral spread from injecting drug users (IDUs). We report on an analysis of data from 1,245 IDUs interviewed in Sydney, Australia in which half of the respondents reported being intoxicated during sex for more than half of their sexual encounters. The most common drugs on which people were intoxicated during sex were heroin, cannabis and alcohol. Predictors of having sex when intoxicated were a lower likelihood of having been in treatment, higher number of sexual partners, sharing injection equipment with more people and more recently, being intoxicated when injecting, and not being a sex worker. The data indicate that having sex while intoxicated is common in these IDUs and that sex under the influence of drugs is part of a more general lifestyle of spending a greater time intoxicated. Targeting of those IDUs who spend a significant amount of time intoxicated and their recruitment into treatment may thus reduce both risky sexual behaviour and risky injecting behaviour.

This paper reports on the incidence of unsafe injecting and the factors which influence this practice in a sample of 1245 Sydney injecting drug users (IDUs). Using a needle and syringe after someone else at some time in the last six months was reported in 41.6% of the sample. Taking into account those who claimed always to clean used needles with virucidal methods, 32.9% had placed themselves at risk of HIV infection from shared needles in the six months prior to interview.Seven factors were predictive of unsafe behaviour. These were (a) the amount spent per week on drugs, (b) the number of times a single needle was used prior to disposal, (c) having shared with a person who is now HIV infected, (d) having a regular sexual partner, (e) the proportion of times high, stoned or drunk when injecting, (f) being part of a group that injects together and (g) having been in prison.

We provide an upper bound on the number of ordered Reidemeister moves required to pass between two diagrams of the same link. This bound is in terms of the number of unordered Reidemeister moves required., 11 pages, 15 figures; fixed minor typographical error

We investigated levels of equipment sharing in injecting drug users in Sydney, Australia, in two consecutive samples recruited in a non-treatment setting using similar methodology in 1989 (n = 1,245) and 1990 (n = 550). Comparison between the two waves of the study indicated that there were consistent and major reductions in percentage of time used equipment was re-used, and number of people from whom used equipment had been accepted. There was a corresponding significant and major increase in use of sterile injection equipment, obtained more frequently in the second sample from needle and syringe exchanges. The proportion of respondents reporting they had never shared equipment rose significantly. These data suggest that there is a continuing increase in the adoption of safer injecting practices and utilisation of needle and syringe exchanges over time in response to the threat of HIV transmission in injecting drug users.

This paper reports on the incidence of risk taking behaviours, and the relationship between risk perception and risk behaviours in a sample of 1245 Sydney injecting drug users (IDUs). Almost all respondents reported engaging in behaviours that placed them at risk of HIV infection: 32.9% through unsafe injecting, 84.4% because of unsafe sexual behaviour and 89.2% because of either injecting or sexual behaviour. Injecting and sexual behaviour were poorly correlated. This study also found that risk perception is unrelated to injecting or sexual behaviours, previous history of sexually transmitted diseases, a range of demographic characteristics including age and gender, and the number of times tested for HIV. Social policy and prevention programs should aim to change unsafe injecting and sexual behaviours directly, rather than attempting to achieve change indirectly by changing risk perception.

The objectives of this study were to describe the patterns of alcohol and recreational drug use of HIV-seropositive homosexual men and to determine the effect of alcohol use on HIV risk-taking behaviour. Of particular interest was the effect of knowledge of HIV status on these behaviours. Information on alcohol and drug use was obtained from 485 HIV-seropositive homosexual and bisexual men presenting to a HIV-antibody testing and medical management clinic. Heavy alcohol use was common, with 46.2% reporting consumption of six or more standard drinks on one day recently. Men who knew that they were HIV infected drank significantly more than those men who had yet to learn of their HIV status at the time of interview. There was clear evidence in this study for a role of alcohol use in HIV risk-taking behaviour. Almost one-third (27%) of the HIV-seropositive men reported unprotected anal intercourse during the previous 3 months with approximately one-third of these (27/76, 35.5%) nominating alcohol as contributing to their high HIV-risk behaviour.

Injecting drug users (IDUs) play a disproportionate role in the spread of HIV given their injecting and sexual contacts, and thereby act as conduits between these risk groups. We investigated differences in risk behaviour and HIV seroprevalence in a Sydney sample of 1,245 IDUs. Significant differences were observed across sexual orientation in HIV serostatus for males, with homosexual men having the highest HIV seroprevalence rate (35%), bisexual men intermediate (12%) and heterosexual men lowest (3%). Sexual HIV risk behaviours were lowest for homosexual men, intermediate for bisexual men, and highest for heterosexual men in the case of condom use: however, for numbers of partners, seroprevalence, and anal sex the trends were reversed. There were no differences across sexual orientation for either sex for injecting drug risk behaviours. Both male and female respondents reported having more than 50% of sexual contacts while under the influence of drugs. This study suggests that risk reduction in the sexual domain has not generalized to the injecting risk domain regardless of sexual orientation, and demonstrates that sexual risk behaviours in IDUs are lowest in homosexual, intermediate in bisexual, and highest in heterosexual IDU men.

This study describes scales which can be used to identify the levels of stress and reward associated with being a AIDS emotional-support volunteer. Four categories of stressors were identified. These were ‘emotional overload’, ‘client problems’, ‘lack of support’ and ‘lack of training’. The reward categories were ‘personal effectiveness’, ‘emotional support’, ‘social support’ and ‘empathy/self-knowing’. There were low, but positive correlations between these stressor scales and other measures of psychological morbidity, the 28-item General Health Questionnaire (GHQ) and the Maslach Burnout Inventory (MBI). Levels of stress and reward were positively correlated and, taken together, the scales may be of use as a measure of the degree of involvement of volunteers in the AIDS care-giving process. Although these scales were derived from items provided from AIDS emotional-support volunteers many of the items may also be relevant to other health workers providing care for people with AIDS.

Objective To test the ability of a modified pulmonary artery (PA) monitoring catheter to detect distal catheter migration. Design Prospective nonrandomized trial. Patients Surgical ICU patients requiring invasive hemodynamic monitoring. Interventions Eight patients received PA catheters modified to include a right ventricular (RV) pressure monitoring port located 7 cm from the tip. Fifteen patients received catheters with an RV port located 10 cm from the tip. Guided by the RV port pressure waveform, catheters were initially positioned so that the RV port was located just proximal to the pulmonic valve. Measurements and main results Pulmonary capillary occlusion pressure (PAOP) could not be obtained in six of the eight patients receiving the 7-cm RV port catheter unless the RV port was advanced into the PA. PAOP was consistently obtained in all 15 patients receiving the 10-cm RV port catheter, with the RV port positioned in the RV. Chest radiographs confirmed a central PA catheter position. In this group, distal migration of the catheter occurred 14 times in eight patients, as detected by appearance of a PA pressure waveform at the RV port. Distal migration was corrected by withdrawal of the catheter until an RV waveform reappeared at the RV port. Conclusions We conclude that distal catheter migration occurs frequently with PA monitoring catheters, but can be detected at the bedside with a catheter modified to include an RV port 10 cm from the tip. This new catheter may add a margin of safety to PA monitoring and lower its overall cost by eliminating the need for chest radiographs ordered solely to confirm catheter tip location.

Self-reported histories of sexually transmissible diseases (STDs) and HIV serostatus were investigated as part of a study of HIV risk behaviour in a sample of 1245 Syndey injecting drug users (IDUs) (mean age 27.5 years) both in and out of treatment. A high lifetime prevalence of STDs was reported in both men and women. For male IDUs, the lowest reported lifetime prevalence of STDs was in heterosexuals, with bisexuals intermediate and homosexuals reporting the highest prevalence. HIV seroprevalence followed the same pattern. For women, bisexuals had the highest reported STD history, heterosexual women were intermediate and homosexual women reported the lowest prevalence. Over one third of the bisexual women reported having been involved in prostitution. These data indicate that over one third of IDU men and over half of IDU women reported at least one STD in their lifetime. The high lifetime prevalence of STDs in IDUs indicates that this group is at increased risk of sexual transmission of HIV, given the importance of STDs as a cofactor. Reducing the prevalence of STDs in IDUs is a possible additional strategy to diminish the spread of HIV among IDUs and from them to non-IDU sexual contacts.

The aim of the study was to investigate symptoms of long-term central nervous system (CNS) toxicity in HIV-positive patients treated with efavirenz (EFV).We carried out a single-centre, cross-sectional case-control study comparing patients treated with EFV for at least 6 months with a matched control group. Self-administered, standardized questionnaires including the Depression, Anxiety and Stress Scales (DASS), the Cognitive Failures Questionnaire (CFQ) and a questionnaire on unusual dreams, insomnia, fatigue, dizziness, depersonalization and derealization were administered.Data for 32 matched pairs were analysed. Significantly higher total stress scores (P=0.008) were found in the EFV group. Of the patients in this group, 19% also reported severe to extremely severe levels of stress (P=0.014), indicating increased difficulty in relaxing, and being more irritable, impatient, agitated and easily upset. Nineteen per cent of patients treated with EFV also reported severe levels of anxiety (P=0.059) as assessed with the DASS scale. This patient group also reported a higher rate of unusual dreams (P=0.049). No significant differences between groups were found for measures of cognitive impairments, fatigue, dizziness, derealization or depersonalization.EFV-treated patients reported higher levels of severe stress and anxiety as well as a higher rate of unusual dreams than patients not treated with EFV. These differences may be an expression of persisting CNS side effects in patients who remain on EFV for a prolonged period.

Herpes virus infections impose considerable morbidity in immunocompetent patients, with 22% of adults in developed countries having been infected with herpes simplex virus 2 (HSV-2) and four cases per 1000 individuals of symptomatic varicella zoster virus (VZV) infections estimated per year.1,2 Symptoms from both HSV and VZV can be effectively reduced with acyclovir therapy. More recently valaciclovir (GlaxoSmithKline, Brentford, London, UK) and famciclovir (Novartis, Basel, Switzerland) have shown similar efficacy in these conditions, with more favourable dosing schedules than acyclovir.3–6 The usage of these two drugs imposes a considerable financial burden on the public healthcare system, with initial treatment courses for HSV costing $A104.51 for valaciclovir and $A135.79 for famciclovir compared to $A89.31 for acyclovir – see http://www.pbs.gov. au/html/healthpro/search/ (accessed 26 April 2007). The Australian Health Insurance Commission spent $A27 816 155 and $A41 761 426 on famciclovir and valaciclovir respectively in the last financial year for HVS-2 and VZV management – see http://www.medicareaustralia.gov.au/statistics/ (accessed 26 April 2007). We therefore sought to determine if there was a perception of differential efficacy between these two commonly prescribed drugs and to determine which clinical characteristics might influence prescribing. In September 2003, an attitudinal survey was undertaken involving 632 metropolitan based primary care clinicians across Australia. The survey questions were prepared by the authors based on published clinical variables that might influence treatment responses, with the survey delivered to clinicians by product representatives from Novartis. The following research questions were asked: ‘Did the clinician believe that either famciclovir or valaciclovir had greater efficacy in certain patients?’ and ‘If so, what patient characteristics were thought to account for this difference (e.g. age, gender, number of episodes, severity or others)?’ This question was asked separately for patients with genital herpes and herpes zoster. Responses were collected by the product representatives within the following 2 weeks and forwarded to the authors for analysis.

The objective of this study is to assess the costs cost-effectiveness and HIV epidemic impact of 3 antiretroviral therapy (ART) policy options. We constructed an epidemiologic model to predict the course of the HIV epidemic in the absence of expanded ART availability. Based on background studies of the willingness to pay for ART among patients with AIDS of the costs to the government of the alternative treatment interventions and of ARTs likely effects on HIV transmission we simulated the consequences of 3 possible alternative government ART policies. A program to reduce the negative consequences of the currently unstructured private-sector provision of ART is the most cost-effective of the 3 options at a 10% discount rate and least cost-effective at a 3% rate. The costs and cost-effectiveness of all options are highly sensitive to the effect of ART on condom use. The design of ART policy should capitalize on the potential of ART to decrease HIV transmission through institutional arrangements that reward effective prevention programs thereby raising the likelihood that treatment has beneficial rather than negative external effects. (authors)

Objectives: Current research is unclear about the most effective pharmacological agents for managing the loss of weight and fat-free mass common in HIV/AIDS. The aim of this study was to compare nandrolone decanoate with placebo and testosterone. Methods: The study was a multicentre randomized double-blind placebo-controlled trial. Three hundred and three adult HIV-positive male patients with a weight loss of 5-15% in the last 12 months, or a body mass index of 17-19 kg/m2, or a body cell mass/height ratio lower than 13.5 kg/m, were randomly assigned to receive nandrolone decanoate (150 mg), testosterone (250 mg) or placebo intramuscularly every 2 weeks for 12 weeks. Fat-free mass, weigth, immune markers and perception of treatment were the main outcome measures. Results: Treatment with nandrolone resulted in significantly greater increases in fat-free mass [mean increase 1.34 kg; 95% confidence interval (CI) 0.60; 2.08 kg] and in weight (mean increase 1.48 kg; 95% CI 0.82; 2.14 kg) compared with placebo. The mean increase in weight with nandrolone of 1.00 kg (95% CI 0.27; 1.74 kg) when compared with testosterone was significant, although the difference in fat free mass did not reach significance (mean increase 0.69 kg; 95% CI-0.13; 1.51 kg). Patient perception of benefit was significantly greater in the nandrolone group when compared with both the placebo and the testosterone groups. Conclusion: Treatment with nandrolone decanoate increased body weight when compared with placebo and testosterone. Nandrolone decanoate treatment resulted in greater increases in fat-free mass than placebo and demonstrated a trend for a significant increase when compared with testosterone.

The rate of nosocomial respiratory syncytial virus (RSV) infection was measured in a large pediatric hospital using an incidence density method. The at-risk days for nosocomial RSV were summed during a defined winter period in which there were 54 admissions with community-acquired RSV infection giving a rate of 2.9 cases per 1,000 at-risk days (95% confidence interval, 0.3-5.4 per 1,000).