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New South Wales has the greatest burden of HIV in Australia, with 2012 and 2013 recording the highest rates of new diagnoses in 20 years. Concurrently, there has been significant changes in antiretroviral treatments and testing paradigms. We compiled a statewide resistance database to characterize changes in HIV-1 resistance mutations over time. Genotypic antiretroviral resistance testing (GART) was performed on request at three reference laboratories using commercial and in-house methods. In total, 7629 HIV-1 polymerase sequences obtained from GART from 2004 to 2013 were retrospectively collated, reformatted, de-identified, and analyzed using Stanford HIVdb program 7.0 and the 2009 World Health Organization (WHO) surveillance drug resistance mutations (SDRMs). Analyses were performed on subgroups of known treatment naives, treatment experienced, and seroconverters. There has been a decrease in overall rates of prevalent drug resistance mutations from 57.8% in 2004 to 21% in 2013. Dual and triple class resistance mutations have decreased from 32.7% in 2004 to 5.8% in 2013 and 16.4% to 1.2%, respectively. In treatment-naive individuals (

Background Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause a wide range of glomerular pathologies. In people with haemophilia, transfusion-associated infections with these viruses are common and definitive pathological diagnosis in this population is complicated by the difficulty of safely obtaining a renal biopsy. Membranous nephropathy (MN) is a common cause of adult onset nephrotic syndrome occurring in both primary and secondary forms. Primary MN is associated with podocyte autoantibodies, predominantly against phospholipase A2 receptor (PLA2R). Secondary disease is often associated with viral infection; however, infrequently with HIV or HCV. Distinguishing these entities from each other and other viral glomerular disease is vital as treatment strategies are disparate. Case presentation We present the case of a 48-year-old man with moderate haemophilia A and well-controlled transfusion-associated HCV and HIV coinfection who presented with sudden onset nephrotic range proteinuria. Renal biopsy demonstrated grade two membranous nephropathy with associated negative serum PLA2R testing. Light and electron microscopic appearances were indeterminant of a primary or secondary cause. Given his extremely stable co-morbidities, treatment with rituximab and subsequent angiotensin receptor blockade was initiated for suspected primary MN and the patient had sustained resolution in proteinuria over the following 18 months. Subsequent testing demonstrated PLA2R positive glomerular immunohistochemistry despite multiple negative serum results. Conclusions Pursuing histological diagnosis is important in complex cases of MN as the treatment strategies between primary and secondary vary significantly. Serum PLA2R testing alone may be insufficient in the presence of multiple potential causes of secondary MN.

International audience; Background: Global HIV-1 genetic diversity and evolution form a major challenge to treatment and prevention efforts. An increasing number of distinct HIV-1 recombinants have been identified worldwide, but their contribution to the global epidemic is unknown. We aimed to estimate the global and regional distribution of HIV-1 recombinant forms during 1990-2015.Methods: We assembled a global HIV-1 molecular epidemiology database through a systematic literature review and a global survey. We searched the PubMed, Embase (Ovid), CINAHL (Ebscohost), and Global Health (Ovid) databases for HIV-1 subtyping studies published from Jan 1, 1990, to Dec 31, 2015. Unpublished original HIV-1 subtyping data were collected through a survey among experts in the field who were members of the WHO-UNAIDS Network for HIV Isolation and Characterisation. We included prevalence studies with HIV-1 subtyping data collected during 1990-2015. Countries were grouped into 14 regions and analyses were done for four time periods (1990-99, 2000-04, 2005-09, and 2010-15). The distribution of circulating recombinant forms (CRFs) and unique recombinant forms (URFs) in individual countries was weighted according to the UNAIDS estimates of the number of people living with HIV in each country to generate regional and global estimates of numbers and proportions of HIV-1 recombinants in each time period. The systematic review is registered with PROSPERO, CRD42017067164.Findings: Our global data collection yielded an HIV-1 molecular epidemiology database of 383 519 samples from 116 countries in 1990-2015. We found that the proportion of recombinants increased over time, both globally and in most regions, reaching 22·8% (7 978 517 of 34 921 639) of global HIV-1 infections in 2010-15. Both the proportion and the number of distinct CRFs detected increased over time to 16·7% and 57 CRFs in 2010-15. The global and regional distribution of HIV-1 recombinants was diverse and evolved over time, and we found large regional variation in the numbers (0-44 CRFs), types (58 distinct CRFs), and proportions (0-80·5%) of HIV-1 recombinants. Globally, CRF02_AG was the most prevalent recombinant, accounting for 33·9% (2 701 364 of 7 978 517) of all recombinant infections in 2010-15. URFs accounted for 26·7% (2 131 450 of 7 978 517), CRF01_AE for 23·0% (1 838 433), and other CRFs for 16·4% (1 307 270) of all recombinant infections in 2010-15. Although other CRFs accounted for small proportions of infections globally (

A 69-year-old man presented to the Emergency Department with 1 day of acute spontaneous vertigo, left-sided tinnitus and hearing loss. He had no otalgia, previous vertigo or hearing problems but did have a background of diabetes and hypertension. On examination, with fixation, there was no nystagmus, but without visual fixation (using Frenzel’s goggles), there was primary position left-beating nystagmus. The horizontal head-impulse test was negative, but his left Dix-Hallpike positional test was positive, provoking a paroxysm of up-beating, torsional nystagmus with vertigo. Otoscopy was normal with no vesicles. Weber’s test was positive to the right and Rinne’s was bilaterally negative. Smooth pursuit, saccades and cerebellar examinations were normal. Audiometry identified a left-sided profound and high-frequency and moderate-to-severe mid-frequency sensorineural hearing loss; right-ear audiometry identified only a mild high-frequency sensorineural hearing loss (figure 1A). He had acoustic reflexes in both ears at normal thresholds. Figure 1 (A) Asymmetric audiogram at initial presentation. Right ear shows a mild high-frequency sensorineural hearing loss, while the left ear shows a sloping mild-to-profound sensorineural hearing loss. (B) Left vestibular loss. Three-dimensional video head impulse at initial presentation shows isolated reduced left posterior semicircular canal vestibulo-ocular reflex gain (0.19) with catch-up saccades. (Gain values are listed to the top right of each individual head-impulse test.) (C) Repeat audiometry at 2 months. In comparison with the original audiogram, the right-ear results showed new upsloping severe-to-mild sensorineural hearing loss below 1 kHz and mild hearing loss above 1 kHz. The left-sided hearing has returned to normal at the low-to-mid frequencies after corticosteroid treatment. (D) Home audiometry over 45 days showing marked fluctuations in the right ear across the low-to-mid frequencies (≤1 kHz, red and orange traces). (E) The left ear shows little fluctuation in hearing loss. (F) Timeline of treatment. There was marked response in the left hearing loss, as …

We characterised the clinical and neuro-otological characteristics of patients with Susac syndrome. The medical records of 30 patients with Susac syndrome were reviewed for details of their clinical presentation and course, neuro-otological symptoms, investigation results including audiology and vestibular function tests, treatment and outcomes. Our findings demonstrate that 29 of our 30 patients with Susac syndrome developed neuro-otological symptoms such as hearing loss, disequilibrium, tinnitus or vertigo during their disease course. Hearing loss was the most common neuro-otological symptom occurring in 93% of patients. A rising configuration of low-frequency greater than the high-frequency sensorineural hearing loss was the most characteristic finding on audiological testing (37% of reviewed audiograms). Disproportionately poor speech discrimination was identified in 20% of cases, and one case demonstrated a retrocochlear pattern on electrophysiological testing. Four patients required hearing aids and a further two patients required a cochlear implant due to severe hearing loss. Two out of two treated patients had improvements in hearing after the prompt administration of corticosteroids, indicating the potential for recoverable hearing loss if relapses are treated early. Effects on vestibular function were variable in ten patients who were tested, with most showing preservation of function despite significant hearing loss. Neuro-otological symptoms in Susac syndrome are almost universal. In the correct clinical context, a rising configuration of low to high-frequency sensorineural hearing loss should prompt consideration of Susac syndrome. Treatment of inner ear symptoms in Susac syndrome requires further research as early immunotherapy may be beneficial.

In HIV-infected individuals on antiretroviral therapy (ART), latent HIV is enriched in CD4 T cells expressing immune checkpoint molecules, in particular programmed cell death-1 (PD-1). We therefore assessed the effect of blocking PD-1 on latency, both in vitro and in vivo.HIV latency was established in vitro following coculture of resting CD4+ T cells with myeloid dendritic cells. Expression of PD-1 was quantified by flow cytometry, and latency assessed in sorted PD-1high and PD-1low/-nonproliferating CD4+ memory T cells. The role of PD-1 in the establishment of latency was determined by adding anti-PD-1 (pembrolizumab) to cocultures before and after infection. In addition, a single infusion of anti-PD-1 (nivolumab) was administered to an HIV-infected individual on ART with metastatic melanoma, and cell-associated HIV DNA and RNA, and plasma HIV RNA were quantified.HIV latency was significantly enriched in PD-1high compared with PD-1low/- nonproliferating, CD4 memory T cells. Sorting for an additional immune checkpoint molecule, T-cell immunoglobulin domain and mucin domain-3, in combination with PD-1, further enriched for latency. Blocking PD-1 prior to HIV infection, in vitro, resulted in a modest but significant decrease in latently infected cells in all donors (n = 6). The administration of anti-PD-1 to an HIV-infected individual on ART resulted in a significant increase in cell-associated HIV RNA in CD4 T cells, without significant changes in HIV DNA or plasma HIV RNA, consistent with reversal of HIV latency.PD-1 contributes to the establishment and maintenance of HIV latency and should be explored as a target, in combination with other immune checkpoint molecules, to reverse latency.

Background Internationally, medical schools have long used a variety of approaches to develop hybrid Problem based learning (PBL) curricula. However, Team-based learning (TBL), has gained recent popularity in medical education. TBL maintains the advantages of small group teaching and learning, but in contrast to Problem-based learning (PBL), does not require large numbers of tutors. In 2016, TBL was introduced to Year 1 of the Sydney Medical Program (SMP).This study sought to compare students’ perceptions of using TBL in place of PBL. Methods Year 1 students (n = 169) completed three PBL and three TBL sessions during one of the following teaching blocks: Musculoskeletal (n = 56), Respiratory (n = 59) or Cardiovascular (n = 54). Student feedback following completion of each block of teaching was collected by questionnaire, using closed and open ended items. Data were analysed using descriptive statistics and thematic analysis. Results In total, 144/169 (85%) of participants completed a questionnaire regarding PBL, and 152/169 (90%) completed a similar questionnaire regarding TBL. The students found positive aspects of their TBL experience to include the smaller group size, the use of readiness assurance tests, immediate feedback from senior clinicians, and time efficiency. In PBL, students reported that variable expertise of tutors; limited direction; and large group size hindered their learning. Conclusions Overwhelmingly, students preferred TBL over PBL, as the optimal teaching strategy. Students found the structure and format of the TBL sessions more conducive to learning, engagement and participation than PBL sessions. Although the use of TBL required an instructional approach, needing direction from the tutor, it remained student-centred, generating a range of positive outcomes. Study results provide confidence to change from PBL to TBL within Year 1 and Year 2 of the SMP in 2017.

Background Rapid changes in medical practice have a large impact on the demands faced by educators in preparing students for future participation in a multifaceted healthcare workforce. Competencies required by today’s medical graduates encompass the ability to effectively collaborate, communicate and problem solve. The learning needs of medical students have also changed over time. Today’s medical students are highly interconnected, enjoying teamwork and collaborative practice, and desire continuous, explicit feedback. They want structured learning activities, with clear expectations, and enjoy a sense of accomplishment on their achievements. The conflation of these issues has seen many medical schools adopt the model of Team-based learning (TBL). Using the conceptual framework of communities of practice, we sought to qualitatively explore students’ and teachers’ experience of TBL in Year 1 of a graduate entry medical program. Methods Convenience sampling was used to select 169/350 (48%) Year 1 students who completed three TBL sessions. Each TBL session was facilitated by three senior clinicians. Following participation in the TBLs, students were invited to attend focus groups, and all facilitators (n = 9) were invited to attend interviews. A coding framework was developed to code the entire dataset, using the theoretical lens of communities of practice. Results 34/169 (20%) of students attended focus groups. Three facilitators (3/9, 33%) were interviewed. Students and facilitators felt the structure and organisation of TBL made students accountable for their learning and team contributions. The combined expertise and clinical experience of facilitators, with immediate feedback helped groups to work both independently and collaboratively. Facilitators found working with their peers in the TBLs to be a rewarding experience. Conclusions The community of practice found in the TBL classes, provided an enriching and rewarding learning environment that motivated students to build on their basic knowledge and apply what had been learnt. The interactions of experienced, senior clinicians as facilitators, sharing their expertise within a clinical context, prompted effective student engagement in learning and understanding. Our change in curriculum design and pedagogy will assist in preparing medical students for demands of the increasingly complex healthcare systems in which they will work.

Background Patients with thymoma with immunodeficiency (TWI)/Good’s syndrome characteristically have evidence of combined immunodeficiency including low or absent B-cells, hypogammaglobulinemia and defects in T-cell mediated immunity. These patients can present with common or opportunistic infections. Case presentation A 54-year-old female was diagnosed with cerebral toxoplasmosis. This occurred on a background of metastatic thymoma previously treated with chemotherapy and myasthenia gravis (MG) treated with mycophenolate mofetil, monthly intravenous immunoglobulin (IVIG) and pyridostigmine. She reported recurrent herpes zoster infection. The patient had clinical and radiological progression of cerebral infection despite completing standard induction and maintenance therapy with sulfadiazine and pyrimethamine. Investigations found a complete absence of B-cells and evidence for hypogammaglobulinemia which, together with evidence of defects in T-cell mediated immunity and thymoma, lead to a diagnosis of TWI/Good’s Syndrome. The patient has undergone prolonged high-dose therapy for toxoplasmosis and a reduction in immunosuppression with no evidence of recurrent toxoplasmosis or flare of MG. Conclusions TWI/Good’s Syndrome should be suspected in patients with thymoma and recurrent, persistent or unusual infections. If suspected serum immunoglobulins and lymphocyte subsets should be measured. These patients may need closer monitoring, higher dose and prolonged treatment of infections, and weaning of concurrent immunosuppression may be considered.

Introduction Rates of new HIV-1 diagnoses are increasing in Australia, with evidence of an increasing proportion of non-B HIV-1 subtypes reflecting a growing impact of migration and travel. The present study aims to define HIV-1 subtype diversity patterns and investigate possible HIV-1 transmission networks within Australia. Methods The Australian Molecular Epidemiology Network (AMEN) HIV collaborating sites in Western Australia, South Australia, Victoria, Queensland and western Sydney (New South Wales), provided baseline HIV-1 partial pol sequence, age and gender information for 4,873 patients who had genotypes performed during 2005–2012. HIV-1 phylogenetic analyses utilised MEGA V6, with a stringent classification of transmission pairs or clusters (bootstrap ≥98%, genetic distance ≤1.5% from at least one other sequence in the cluster). Results HIV-1 subtype B represented 74.5% of the 4,873 sequences (WA 59%, SA 68.4%, w-Syd 73.8%, Vic 75.6%, Qld 82.1%), with similar proportion of transmission pairs and clusters found in the B and non-B cohorts (23% vs 24.5% of sequences, p = 0.3). Significantly more subtype B clusters were comprised of ≥3 sequences compared with non-B clusters (45.0% vs 24.0%, p = 0.021) and significantly more subtype B pairs and clusters were male-only (88% compared to 53% CRF01_AE and 17% subtype C clusters). Factors associated with being in a cluster of any size included; being sequenced in a more recent time period (p3) was associated with being sequenced in a more recent time period (p = 0.05) and being male (p = 0.008). Conclusion This nationwide HIV-1 study of 4,873 patient sequences highlights the increased diversity of HIV-1 subtypes within the Australian epidemic, as well as differences in transmission networks associated with these HIV-1 subtypes. These findings provide epidemiological insights not readily available using standard surveillance methods and can inform the development of effective public health strategies in the current paradigm of HIV prevention in Australia.

Background In Australia, government-subsidised treatment of pulmonary arterial hypertension (PAH) is limited to monotherapy. Recent international guidelines advocate that initial combination therapy be considered for all symptomatic PAH patients. We sought to characterise “real-life” outcomes in PAH patients initiated on monotherapy. Methods We performed a retrospective analysis of 100 consecutive PAH patients at a single centre, who were commenced on monotherapy for PAH between 2004 and 2015. The composite clinical endpoint of ‘treatment failure’ was prospectively defined as (1) >15% fall in 6-minute walk distance on follow-up, (2) physician judgement of inadequate treatment response, (3) adverse drug effect requiring cessation, (4) death or transplantation. Results At initiation of therapy, mean age was 54 ± 18 years and underlying diagnoses included idiopathic (36%), connective tissue disease associated (37%), and congenital heart disease associated-PAH (25%). Baseline 6MWD was 360 ± 140 m and 75% were in either New York Heart Association functional class III or IV. Over median follow-up of 38 months (IQR 20–67), 62% of subjects met criteria for a clinical failure event. Median time to monotherapy failure was 24 months (95% CI 14–34) with death or transplantation being the most common clinical failure event. Estimated 1-, 3- and 5-yr survivals from time of treatment initiation were 92%, 75% and 66%. Conclusion The majority of patients failed initial monotherapy therapy within two years of treatment initiation. Broader access to approved PAH agents is needed to enable combination therapy in line with evidence based international guidelines.

BACKGROUND: Patients with systemic lupus erythematosus have T-cell dysfunction that has been attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. We assessed safety, tolerance, and efficacy of sirolimus in a prospective, biomarker-driven, open-label clinical trial. METHODS: We did a single-arm, open-label, phase 1/2 trial of sirolimus in patients with active systemic lupus erythematosus disease unresponsive to, or intolerant of, conventional medications at the State University of New York Upstate Medical University (Syracuse, NY, USA). Eligible participants (aged ≥18 years) had active systemic lupus erythematosus fulfilling four or more of 11 diagnostic criteria defined by the American College of Rheumatology. We excluded patients with allergy or intolerance to sirolimus, patients with life-threatening manifestations of systemic lupus erythematosus, proteinuria, a urine protein to creatinine ratio higher than 0·5, anaemia, leucopenia, or thrombocytopenia. Patients received oral sirolimus at a starting dose of 2 mg per day, with dose adjusted according to tolerance and to maintain a therapeutic range of 6–15 ng/mL. Patients were treated with sirolimus for 12 months. Safety outcomes included tolerance as assessed by the occurrence of common side-effects. The primary efficacy endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI). Blood samples of 56 matched healthy individuals were obtained as controls for immunobiological outcomes monitored at each visit. The primary efficacy endpoint was assessed in all patients who completed 12 months of treatment, and all patients who received at least one dose of treatment were included in the safety analyses. This trial is registered with ClinicalTrials.gov, number NCT00779194. FINDINGS: Between March 9, 2009, and Dec 8, 2014, 43 patients were enrolled, three of whom did not meet eligibility criteria. 11 of the 40 eligible patients discontinued study treatment because of intolerance (n=2) or non-compliance (n=9). SLEDAI and BILAG disease activity scores were reduced during 12 months of treatment in 16 (55%) of 29 patients who completed treatment. Mean SLEDAI score decreased from 10·2 (SD 5·6) at enrolment to 4·8 (4·5) after 12 months of treatment (p

Long-lived latently infected resting CD4+ T cells are the main reason why current antiretroviral therapy (ART) is unable to cure HIV infection [1]. Recent work has suggested that the expression of immune checkpoint markers, such as programmed death-1 (PD1), may play a role in viral persistence on ART via either suppression of virus transcription and/or reduced HIV-specific T cell activity [2,3], but the role of cytotoxic T lymphocyte antigen 4 (CTLA-4 or CD152) in HIV persistence on ART is not clear. Ipilimumab (Yervoy, Bristol-Myers Squibb, New York, New York) is a human immunoglobulin G1 antibody to CTLA-4 that inhibits binding of CTLA-4, expressed on activated T cells and regulatory T cells (Tregs), to its ligands CD80 and CD86. The drug is used to treat metastatic melanoma and has been associated with multiple changes in immune function thought to enhance antitumor T cell function [4]. In HIV-infected individuals, CTLA-4 expression on CD4+ T cells correlates with HIV disease progression [5], and loss of HIV-specific CD4+ T cell function can be reversed in vitro by CTLA-4 blockade [5–7]. In a simian immunodeficiency virus (SIV) macaque model, CTLA-4 blockade led to an increase in T-cell activation and viral replication [8]. Here, we describe changes in the HIV reservoir in an HIV-infected patient on ART who received ipilimumab for the treatment of metastatic melanoma. At initiation of ipilimumab treatment in October 2013 for disseminated melanoma, the patient was a 51-year-old man diagnosed with HIV in 1986 and with a CD4+ nadir of 159 cells/μl in 1995. He was on ART since 1996 and plasma HIV RNA was less than 400 copies/ml from 2004 and less than 20 copies/ml from July 2012 (Fig. 1a). He received four doses of ipilimumab 3 mg/kg given at three-weekly intervals. Fig. 1 Clinical details and changes and impact of ipilimumab on virological and immunological parameters Whilst receiving ipilimumab, there was no overall change in plasma HIV RNA as measured by the Roche viral load assay [lower limit of detection (LLOD) = 20 copies/ml; Fig. 1c]. Using a sensitive single-copy HIV RNA assay (SCA) (LLOD = 0.3 copies/ml) [9], there was a cyclical decrease in plasma HIV RNA following each infusion and an overall decline from 60 to 5 copies/ml (Fig. 1c). Given more frequent sampling was performed with the SCA, we believe that longitudinal changes over time were best assessed with this assay. There was an increase in CD4+ T cells after each infusion (overall change from 610 to 900 cells/μl) (Fig. 1b). This increase was predominantly in total memory (Fig. 1d) and effector memory CD4+ T cells (Fig. 1e). Postinfusion increases in CD4+ T-cell activation were seen as measured by human leukocyte antigen-DR and CD38 and CCR5 expression (Fig. 1f). There were transient increases in CD8+ T cells following the second and third infusions, but no overall change in CD8+ T cell activation (Fig. 1g). Cell-associated unspliced HIV RNA in sorted CD4+ T cells was quantified with increases observed following the first and second infusions, with a maximum change from baseline of 19.6-fold (Fig. 1h). The changes in cell-associated unspliced HIV RNA was greater than those recently reported, following the administration of the histone deacetylase inhibitors vorinostat [10,11] or panobinostat [12], or following disulfiram [13]. There was no change in cell-associated HIV DNA (Fig. 1i), but any change in the small proportion of cells with HIV DNA containing inducible proviruses [14] may not have been detectable with the assays used here. Acknowledging the limitations deriving from this being a single case, we speculate the increase in cell-associated unspliced RNA could have been due to mechanisms, including an increase in HIV RNA transcription secondary to blocking the inhibitory effects of CTLA-4 on T cell transcription, similar to that described following ex-vivo anti-PD1 treatment of CD4+ T cells from HIV-infected patients on ART [15]; redistribution or expansion of effector memory CD4+ T cells that may have a higher ratio of cell-associated HIV RNA to HIV DNA [16] (Satish Pillai, San Francisco, UCSF, San Francisco, California, personal communication); or redistribution or expansion of activated T cells including Tregs. The increase in cell-associated unspliced HIV RNA and decline in SCA was intriguing, perhaps mediated by elimination of latently infected CD4+ T cells that were induced to express viral antigens. But the rapidity of the decline in SCA makes this somewhat unlikely. Blockade of CTLA-4 with ipilimumab in an HIV-infected patient on ART had significant effects on the total number and phenotype of CD4+ T cells and induced a profound increase in cell-associated unspliced HIV RNA with onset after the first dose and was associated with subsequent decline in plasma HIV RNA. Further studies are warranted to determine if ipilimumab could play a role in eliminating latently infected cells in HIV-infected patients on ART.

Background Pulmonary arterial hypertension (PAH) is an increasingly recognised serious illness with insidious onset, delayed diagnosis, complex diagnostic algorithms and poor prognosis, but with recently available effective treatments. Aims To efficiently diagnose and to offer treatment for PAH, we established a multidisciplinary service in 2005, where patients attend a clinic staffed by specialists in cardiology, respiratory medicine, rheumatology and immunology in a tertiary referral hospital setting. Methods We studied the first 200 patients referred. Serology, echocardiography, lung function tests, high-resolution computed tomography, World Health Organisation Class determination and 6-min walk tests and/or right heart catheterisation were performed, as clinically indicated. Results Of the 200 patients seen, 66 had confirmed pulmonary hypertension (mean pulmonary artery pressure > 25 mmHg) diagnosed on echocardiography ± right heart catheterisation. Of these patients, 58 had catheter-proven PAH (mean pulmonary artery pressure > 25 mmHg with mean wedge pressure < 15 mmHg). Underlying diagnoses for the confirmed PAH patients were idiopathic (32), scleroderma-associated (14), other connective tissue disease (4) and associated with congenital heart disease (8). Patients with confirmed PAH were commenced on PAH-specific therapy – initially bosentan in the majority but sildenafil, and iloprost were occasionally used initially for patient-specific reasons. Median time from when the patient first called the clinic to prescription of therapy was 16 days (interquartile range; 0–31 days). All surviving patients with PAH have attended for regular 6-monthly follow-up visits with a 100% retention rate up to 4 years. Conclusion A multidisciplinary clinic can provide efficient diagnosis and rapid triage to PAH-specific therapy, if appropriate. Retention rates remain high, at follow up.

Background Despite virally suppressive combination antiretroviral therapy (cART), some HIV-infected patients exhibit suboptimal CD4(+) T-cell recovery. This study aimed to determine the effect of intensification of cART with raltegravir or addition of hyperimmune bovine colostrum (HIBC) on CD4(+) T-cell count in such patients. Methods We randomized 75 patients to 4 treatment groups to receive raltegravir, HIBC, placebo, or both raltegravir and HIBC in a factorial, double-blind study. The primary endpoint was time-weighted mean change in CD4(+) T-cell count from baseline to week 24. T-cell activation (CD38(+) and HLA-DR(+)), plasma markers of microbial translocation (lipopolysaccharide, 16S rDNA), monocyte activation (soluble (s) CD14), and HIV-RNA (lowest level of detection 4 copies/mL) were monitored. Analysis was performed using linear regression methods. Results Compared with placebo, the addition of neither raltegravir nor HIBC to cART for 24 weeks resulted in a significant change in CD4(+) T-cell count (mean difference, 95% confidence interval [CI]: 3.09 cells/μL, -14.27; 20.45, P = .724 and 9.43 cells/μL, -7.81; 26.68, P = .279, respectively, intention to treat). There was no significant interaction between HIBC and raltegravir (P = .275). No correlation was found between CD4(+) T-cell count and plasma lipopolysaccharide, 16S rDNA, sCD14, or HIV-RNA. Conclusion The determinants of poor CD4(+) T-cell recovery following cART require further investigation. Clinical trials registration ClinicalTrials.gov identifier: NCT00772590, Australia New Zealand Clinical Trials Registry: ACTRN12609000575235.

Susac's syndrome (SS) is the triad of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss. While rare, it has become increasingly recognised since characteristic ‘snowball’ corpus callosum lesions were appreciated on MRI.1 We present clinical and histopathological findings on three patients with SS. Our findings demonstrate a T-cell-mediated inflammatory contribution to lesion pathogenesis. Treatment with the tumour necrosis factor (TNF) inhibitor, infliximab was beneficial in two patients, including in one previously reported,2 and in another who failed rituximab. This report provides a histological rationale for the observed benefit of infliximab, and suggests that infliximab should be considered as an adjunct therapy in patients with refractory SS. Three patients with SS most recently diagnosed among the authors’ practices who had undergone brain biopsy as part of their diagnostic clinical workup were identified. The clinical features, radiology, treatment and outcomes for the three patients are presented as online supplementary data (tables S1–S5 and figures S1 and S2). Extensive serum autoantibody screening was negative. Headache was present in all patients, highlighting the fact that it is a common manifestation of encephalopathy in SS. All three cases reported relatively non-specific auditory and visual symptoms, emphasising that fluorescein angiography±audiology testing should be considered in the diagnostic workup of patients with unexplained encephalopathy. Two patients underwent cerebellar biopsies and one a frontal lobe biopsy. One biopsy was from a treatment-naive patient (case 1). All contained variable numbers of wedge-shaped microinfarcts surrounded by microglia. In cerebellar biopsies (cases 1 and 3), …

Seven hundred and four HIV-1/2-positive, antiretroviral therapy (ART) naïve patients were screened for HTLV-1 infection. Antibodies to HTLV-1 were found in 32/704 (4.5%) of the patients. Each co-infected individual was matched with two HIV mono-infected patients according to World Health Organization clinical stage, age ±5 years and gender. Key clinical and laboratory characteristics were compared between the two groups. Mono-infected and co-infected patients displayed similar clinical characteristics. However, co-infected patients had higher absolute CD4+ T-cell counts ( P = 0.001), higher percentage CD4+ T-cell counts ( P < 0.001) and higher CD4/CD8 ratios ( P < 0.001). Although HIV plasma RNA viral loads were inversely correlated with CD4+ T-cell-counts in mono-infected patients ( P < 0.0001), a correlation was not found in co-infected individuals ( P = 0.11). Patients with untreated HIV and HTLV-1 co-infection show a dissociation between immunological and HIV virological markers. Current recommendations for initiating ART and chemoprophylaxis against opportunistic infections in resource-poor settings rely on more readily available CD4+ T-cell counts without viral load parameters. These guidelines are not appropriate for co-infected individuals in whom high CD4+ T-cell counts persist despite high HIV viral load states. Thus, for co-infected patients, even in resource-poor settings, HIV viral loads are likely to contribute information crucial for the appropriate timing of ART introduction.

This study assessed the relationship between changes in CD4 T-cell count, HIV Viral Load (VL) level and evolutionary patterns in Antiretroviral (ARV) resistance mutations of circulating HIV in those with persistent viraemia despite treatment. The study examined the dynamics of change in resistance mutations to explore potential predictors of evolution in the circulating virus over a prolonged period. Four longitudinal blood samples from 29 HIV-infected Australian patients at RPAH are analysed for the presence of genotypically resistant HIV virus. The subjects had CD4 cells counts (40-670 cells/mm(3)), VL levels (1.7-5.7 log(10) copies/ml), drug resistance mutations, and had been treated with ARV regimens for varying periods between February 1998 and June 2005 (i.e., 88 months). Parametric and nonparametric tests were used to examine changes in CD4 T-cell counts and VL levels, and in frequencies of mutations at different sample points. Nonparametric LOESS fitting curves were used to analyse changes in CD4 T-cell counts and VL levels. During the study period, changes in mean values of CD4 cell counts and VL levels in patients displaying an evolving genotypic resistance profile differed from those without evidence of an evolving mutational pattern; applied for both Reverse-Transcriptase (RT) and Protease (PR) gene profiles. In patients with Evolution-of-Resistance (EoR) at the RT site, there was a significant decrease in mean CD4 cell count during the first 36 months (-194 cells/mm(3), P=0.0466) but no significant change in the last 52 months or thereafter (-10 cells/mm(3), P=0.8464). Conversely, in patients with EoR at the PR site, there was no significant change in mean CD4 cell count during the first 36 months (-30 cells/mm(3), P=0.6187) but a significant decrease (-155 cells/mm(3), P=0.0348) thereafter. In patients without EoR at the RT site, there was no significant change in mean CD4 count during the first 36 months (-12 cells/mm(3), P=0.8371), however, a significant increase in mean CD4 cell count occurred thereafter (+242 cells/mm(3), P=0.0077). Similarly, in patients without EoR at the PR site there was no significant change in mean CD4 count during the first 36 months (-19 cells/mm(3), P=0.6647) and there was a significant increase in the last 52 months (+145 cells/mm(3), P=0.0348). The only significant decrease in mean value of VL levels occurred in patients without EoR associated with NRTIs thereafter (-1.33 log(10) copies/ml, P=0.0477), while no significant changes in mean value of VL levels in patients with/without EoR associated with any ARV drugs at any other time points (-0.65 to +0.15 log(10) copies/ml, P=0.1855 to 0.7958). Low CD4 cell counts (250 cells/mm(3)) and high VL levels (4.50 log(10) copies/ml) in the early stage of HIV infection, a significant decrease in CD4 cell counts during the first 36 months (-50 or more cells/mm(3)), and high frequencies of mutations during the first 36 months of antiretroviral regimen (3 mutations) emerged as potential predictive factors of EoR associated with NRTI/PRI agents thereafter. Stable VL in the first 36 months correlated with lack of lability of resistance mutations thereafter.

Objectives To assess the prevalence, distribution and clinical correlates of myocardial fibrosis, as detected by cardiac magnetic resonance (CMR), in systemic lupus erythematosus (SLE). Methods Forty-one subjects (average age 39 ± 12 years and 80% female) with SLE underwent CMR imaging at 1.5T, using late gadolinium enhancement (LGE) to quantify the area of myocardial fibrosis in the left ventricle (LV). Subjects also underwent transthoracic echocardiography (TTE) and exercise testing. Results LGE was detected in 15/41 subjects, 11 with localized LGE (15% LV mass). The commonest site of LGE was the interventricular septum, with all but one case demonstrating an intramural or inflammatory pattern. The mean age of the >15% LGE group (55 ± 15 years) was significantly higher than the 15% demonstrated a reduced E/A ratio of 0.9 ± 0.4 relative to the 15% LGE group. Conclusions Mid-wall myocardial fibrosis occurs frequently in SLE and is strongly associated with advancing subject age, but not with SLE duration or severity. Extensive LGE may be associated with diastolic dysfunction and impaired exercise capacity, although this may be an epiphenomenon of age. Cardiac magnetic resonance with quantitative assessment of LGE may provide a basis for cardiac risk stratification in SLE.

Inferior alveolar nerve blocks are commonly performed for dental anaesthesia. The procedure is generally safe with a low rate of complications. We report a patient with a reproducible, delayed-onset sensory deficit associated with contrast-enhancing lesions in the trigeminal nerve, pons and medulla following inferior alveolar nerve local anaesthesia. We propose that this previously undescribed condition is a form of Type IV hypersensitivity reaction.

Background: The co-existence of autoimmunity and primary antibody deficiency in some individiuals is intriguing. The transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) gene (TNFRSF13B) has been implicated in both autoimmunity and primary antibody deficiency to varying extents in mice and humans. However, the phenotype described in mice with TNFRSF13B polymorphisms has not been entirely consistent with patients with similar orthologous polymorphisms.Objective: To further understand the relationship between TNFRSF13B variants and PAD and autoimmunity, we set out to determine the association of the two most common TNFRSF13B polymorphisms with autoimmunity and immunodeficiency, in patients with primary antibody deficiency and SLE.Method: We genotyped the C104R and A181E polymorphisms of TNFRSF13B in193 individuals and 144 controls from the Australian and New Zealand Antibody Deficiency Allele (ANZADA) Study, 107 patients from the Australian Point Mutation in Systemic Lupus Erythematosus (APOSLE) study, 169 patients with SLE from a European population, and 263 European controls. We were also able to determine TNFRSF13B genotypes for family members for nine of twelve pedigrees with primary antibody deficiency identified with TNFRSF13B variants.Results: The total number of TNFRSF13B variants in the primary antibody deficiency cohort was significantly higher than in the control group (p=0.0089; OR 9.481 [95% CI 1.218−73.81]). Similar results were obtained when patients with systemic lupus erythematosus were analysed. TNFRSF13B variants were strongly associated with SLE (p=0.0161, OR 3.316 [95% CI 1.245-8.836]). Familial analysis revealed incomplete penetrance of the TNFRSF13B variants.Conclusion: Taken together, the two most common TNFRSF13B variants are associated with primary antibody deficiency and systemic lupus erythematosus.

Objectives: To investigate (i) differences in dietary fat and energy intake between those reporting and those not reporting fat redistribution syndrome (FRS), and (ii) the relationship between dietary fat, total energy intake, serum biochemistry and the clinical characteristics of the syndrome. Design: A cross-sectional study. Setting: Outpatient service of a tertiary referral hospital, Sydney, Australia. Patients and methods: Dietary intake, serum lipids and insulin resistance and body composition (fat-free mass, fat mass, waist-to-hip ratio; WHR) were determined in 100 HIV-positive patients whose FRS status was classified on the basis of self-report of body composition changes, verified by clinical examination. Results: There was no significant difference in total or saturated dietary fat intake when grouped by FRS status. There was no significant correlation between dietary saturated or total fat intake and the serum or body composition parameters measured. Total energy intake was higher in those patients reporting FRS (14 575 versus 12 283 kJ, P = 0.037) after adjustment for age, smoking and exercise status. Conclusion: There appears to be no relationship between either dietary saturated or total fat intake and the serum or body composition parameters characteristic of FRS; however, the total energy intake was significantly higher in those with FRS. The nature of the relationship between total energy intake and FRS (cause or effect) warrants further investigation.

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.

The safety and activity of outpatient-based continuous intravenous interleukin-2 (CIV IL-2) or a slow-release, polyethylene glycol (PEG)-modified IL-2 were studied in human immunodeficiency virus (HIV)-infected persons with CD4 cell counts between 200 and 500/mm3. One hundred fifteen patients were randomized to antiretroviral therapy plus cyclical CIV IL-2 (n = 27), subcutaneous PEG IL-2 (n = 58), or no IL-2 (n = 30). Toxicity withdrawal rates were low (4% for CIV IL-2 and 7% for PEG IL-2). There were median CD4 cell count increases of 359 and 44 cells/mm3 and a decline of 46 cells/mm3 in the 3 groups, respectively, over 1 year (P < .0001 for each intergroup comparison). CD4 cell count increases were greatest in those with lower HIV RNA load. Delayed-type hypersensitivity scores increased and HLA-DR expression on CD8 cells decreased significantly with IL-2 therapy. HIV RNA levels were unaffected. IL-2 therapy may expand the existing immune repertoire but not immediately reconstitute lost immune function.

Background Drug rash with eosinophilia and systemic symptoms (DRESS) is a severe drug reaction characterised by rash, eosinophilia and systemic involvement.

We report the case of a 30-year-old woman who failed to achieve diagnostic Western blot criteria for HIV-1 infection until 21 months after her initial presentation. This case highlights the importance of suspecting delayed HIV seroconversion in cases with persistently indeterminant Western blots.

Prolonged acute spontaneous vertigo can be secondary to acute vestibular neuritis or posterior circulation ischaemia. We present a 66-year-old man who first developed an acute vestibular syndrome with profound unilateral hearing loss 34 years ago. First treated as vestibular neuritis, he subsequently developed manifestations of Behcet’s disease, including mouth ulcers, genital ulcers and erythema nodosum over a period of 10 years. Subsequently, sudden sensorineural hearing loss affecting his only hearing ear responded to immunomodulation, confirming an autoimmune cause for the audiovestibular symptoms. This report serves as a reminder that vestibular neuritis seldom causes hearing loss; ischaemic, infective and autoimmune causes should be sought when an acute vestibular syndrome is accompanied by hearing impairment.

Bickerstaff's encephalitis is a syndrome of ophthalmoplegia, ataxia and impaired consciousness commonly associated with serum GQ1b antibodies. We describe a patient with seropositive Bickerstaff's encephalitis who did not respond either to plasma exchange or intravenous immunoglobulin but recovered following adjunct treatment with the anti-CD 20 monoclonal antibody, Rituximab. There was a concomitant reduction in serum GQ1b antibodies associated with improvement. Interestingly, GQ1b antibody was also detected in CSF. These findings have potentially significant clinical and immunopathological implications.

The 1858T allele of protein tyrosine phosphatase nonreceptor type 22 (PTPN22; R620W) exhibits one of the strongest and most consistent associations with sporadic autoimmune disease. Although autoimmunity is common in patients with primary antibody deficiency (PAD), it remains unknown whether its pathogenesis is similar when it arises in this context compared with in immunocompetent patients.We set out to determine whether the 1858T allele of PTPN22 was associated with PAD or with autoimmunity in the context of PAD.We genotyped rs2476601 (g.1858CT), a single nucleotide polymorphism encoding substitution of arginine for tryptophan in PTPN22 (R620W), in 193 patients with PAD and 148 control subjects from an Australian cohort. We also performed a subgroup analysis according to the presence of autoimmunity and B-cell phenotypes.C/T and T/T PTPN22 genotypes were more common in patients with PAD than in the matched control subjects (C/T, 18.1% vs 9.5%; T/T, 1.04% vs 0.6%). The T allele was associated with an increased risk of PAD relative to control subjects (odds ratio, 2.10; 95% CI, 1.11-4.00). The distribution of genotypes in control subjects was similar to those reported previously and did not deviate significantly from Hardy-Weinberg equilibrium. We found a strong association between the 1858T allele and PAD with coexistent autoimmune diseases. In patients with PAD and autoimmunity, 16 (43.2%) of 37 had at least one T allele of PTPN22 compared with 27 (17.3%) of 156 with the C/C genotype (P=.0014; odds ratio, 3.64; 95% CI, 1.68-7.88). We found no evidence that this effect was mediated by enrichment of CD21low B cells.The 1858T PTPN22 allele is strongly associated with autoimmunity in patients with PAD.

Papers with focus on biomedical data analysis have investigated the initiation of HIV treatment on the basis of several factors including the patient's clinical and immunological state, mental health and the likelihood of adherence to treatment. Here we focus on a different domain, namely the decision whether to change treatment based on sequential laboratory test indicators of the patient. In this paper, we give attention to CD4 and blood viral load-based parameters since they have been shown to be significant disease indicators. We develop an SVM-based method and show that our method provides results consistent with guidelines built on clinical knowledge of the impact of various factors on treatment response, and more importantly, indicates which factors contribute the most to the decision via bootstrap analysis. Among our findings are that CD4 T-cells and HIV-1 viral load absolute levels are strong contributors, while CD4 T-cell and blood viral load sequential changes are weaker contributors.

Susac's syndrome is the clinical triad of encephalopathy, branch retinal artery occlusions and sensorineural hearing loss (Susac 1994) [1]. It occurs predominantly in young females and is believed to be an immune-mediated endotheliopathy of small vessels of the brain, retina and cochlea (Neumayer et al. 2009) [2]. Early, aggressive, and sustained immunosuppressive therapy has been recommended for Susac's syndrome and anecdotal evidence has suggested a therapeutic role for monoclonal antibodies (Rennebohm et al. 2008, Lee and Amezcua 2009) [3,4]. We report a case of Susac's syndrome in which the patient improved immediately after tumour necrosis factor (TNF) inhibition with the monoclonal antibody, infliximab.

This paper presents the development and application of a novel algorithm for the detection and classification of the adaptive and neutral evolutionary patterns associated with HIV drug resistance. Here, the Bayesian theorem will be used to predict the prevalence of an evolutionary pattern over a population to determine the class of its behaviour, whether it arose predominantly from neutral evolution, positive selection or negative selection. As an illustration, we will explain the algorithmic procedure in an application to real data, focusing on two- and three-mutation patterns that confer resistance to a drug agent.

Our aim was to compare the assault characteristics of victims presenting to a sexual assault service who were prescribed HIV post-exposure prophylaxis (HIV PEP) with those not prescribed HIV PEP. A retrospective review was carried out of the medical records of victims who were seen over a 12-month period in 1999/2000. HIV PEP may have been potentially appropriate for 117 victims, of whom nine (7.7%) were prescribed PEP (eight women, one man). There was a trend for prescription of PEP to depend on the type of assault, with those suffering anal penetration most likely to be prescribed PEP, followed by those with vaginal, and then oral penetration ( P=0.08). Those who gave a history of oral or vaginal mucosal contact with ejaculate were more likely to receive PEP compared with those in whom ejaculation occurred at a non-mucosal site ( P=0.03). Most prescribed PEP regimens involved three antiretroviral drugs. In this study, HIV PEP, when prescribed, was in accord with existing guidelines. Future studies should aim to better document HIV seroconversions in victims of sexual assault and HIV seroprevalence in assailants.

Often an underlying disorder (such as haemophilia) creates special management issues for people with medically acquired HIV. Although the risk of infection through donated biological materials is now slight, an unknown number of undiagnosed cases remain in the community.

Objectives To analyse clinical features and predictors of survival for AIDS-related non-Hodgkin's lymphoma (NHL) in the era of highly active antiretroviral therapy (HAART), compared to earlier in the HIV epidemic. Methods All AIDS-NHL cases diagnosed at three inner Sydney hospitals caring for people with AIDS during 1985–2001 were identified through medical record searches. Demographic, clinical, immunological and histopathological information was recorded. Year of NHL diagnosis was grouped into three periods, corresponding to whether monotherapy (1985–1991), dual therapy (1992–1995) or HAART (1996–2001) was the main treatment for HIV infection. Statistical comparisons were made between the pre-HAART and post-HAART eras. Results Three hundred cases of AIDS-NHL were identified. Divergent trends were identified for systemic and primary central nervous system (CNS) NHL. For systemic NHL, the CD4 count at NHL diagnosis increased markedly to 208 cells/μL in the post-HAART era (P=0.014) and there was a trend towards presentation as the first AIDS-defining illness (69%, P=0.053), and as earlier stage NHL disease (42%, P=0.048). Median survival time increased from 4.2 months in 1985–1991 to 19 months in the post-HAART era (P