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1.  Quality of life assessment among HIV-positive persons entering the INSIGHT Strategic Timing of AntiRetroviral Treatment trial 
HIV medicine  2015;16(0 1):88-96.
With HIV treatment prolonging survival and HIV managed as a chronic illness, quality of life (QOL) is important to evaluate in persons living with HIV (PLWH). We assessed QOL at study entry in the Strategic Timing of AntiRetroviral Treatment clinical trial of antiretroviral-naive PLWH with >500 CD4 cells/μL.
QOL was assessed with: 1) visual analogue scale (VAS) for self-assessment of overall current health; 2) SF-12V2 Health Survey®, summarised into eight individual QOL domains plus component summary scores for physical health (PCS) and mental health (MCS). The VAS and eight domain scores were scaled 0–100. Mean QOL measures were calculated overall and by demographic, clinical and behavioural factors.
4631 participants completed the VAS and 4119 the SF-12. Mean VAS score was 80.9 ±15.7. Mean SF-12 domain scores were lowest for vitality (66.3 ±26.4) and mental health (68.6 ±21.4), and highest for physical functioning (89.3 ±23.0) and bodily pain (88.0 ±21.4). Using multiple linear regression, PCS scores were lower (p<0.001) for Asians, North Americans, females, older age, less education, longer duration of known HIV, alcoholism/substance dependence, and body mass index ≥30 kg/m2. MCS scores were highest (p<0.001) for Africans, South Americans, and older age and lowest for females, current smokers, and alcoholism/ substance dependence.
In this primarily healthy population, QOL was mostly favorable, emphasising importance that HIV treatments do not negatively impact QOL. Self-assessed physical health was higher than mental health. Factors such as older age and geographic region have different influences on perceived physical and mental health.
PMCID: PMC4341945  PMID: 25711327
Quality of life; HIV; antiretroviral therapy
2.  Influence of Equatorial CH⋅⋅⋅O Interactions on Secondary Kinetic Isotope Effects for Methyl Transfer 
DFT calculations for methyl cation complexed within a constrained cage of water molecules permit the controlled manipulation of the “axial” donor/acceptor distance and the “equatorial” distance to hydrogen‐bond acceptors. The kinetic isotope effect k(CH3)/k(CT3) for methyl transfer within a cage with a short axial distance becomes less inverse for shorter equatorial C⋅⋅⋅O distances: a decrease of 0.5 Å results in a 3 % increase at 298 K. Kinetic isotope effects in AdoMet‐dependent methyltransferases may be m∧odulated by CH⋅⋅⋅O hydrogen bonding, and factors other than axial compression may contribute, at least partially, to recently reported isotope‐effect variations for catechol‐O‐methyltransferase and its mutant structures.
PMCID: PMC4770435  PMID: 26823274
computational chemistry; enzyme catalysis; hydrogen bonds; isotope effects; methyl transfer
3.  Dietary Lecithin Supplementation Can Improve the Quality of the M. Longissimus thoracis 
Simple Summary
Meat tenderness and texture can be influenced by the connective tissue content. Dietary lecithin offers a means of improving fat digestibility of pigs and reducing the connective tissue of pork. This feeding study confirmed that dietary lecithin decreased the chewiness and improved the fatty acid composition of pork without impacting on growth performance of pigs. Therefore, dietary lecithin supplementation has the potential to improve the quality attributes of pork.
Forty crossbred (Large White × Landrace × Duroc) female pigs (16.4 kg ± 0.94 kg) were used to investigate the effect of dietary lecithin supplementation on growth performance and pork quality. Pigs were randomly allocated to a commercial diet containing either 0, 3, 15 or 75 g lecithin/kg of feed during the grower and finisher growth phase. Pork from pigs consuming the diets containing 15 g and 75 g lecithin/kg had lower hardness (P < 0.001) and chewiness (P < 0.01) values compared to the controls. Dietary lecithin supplementation at 75 g/kg significantly increased (P < 0.05) the linoleic acid and reduced (P < 0.05) the myristic acid levels of pork compared to the control and the 3 g/kg and 15 g/kg lecithin supplemented treatments. Pigs fed the 75 g/kg lecithin supplemented diet had lower plasma cholesterol (P < 0.05) at slaughter compared to pigs fed the control diet and the 3 g/kg and 15 g/kg lecithin supplemented treatments. These data indicate that dietary lecithin supplementation has the potential to improve the quality attributes of pork from female pigs.
PMCID: PMC4693209  PMID: 26610579
lecithin; pork quality; texture; compression
4.  Will measuring mechanical properties help us understand solid-state reactions? 
IUCrJ  2015;2(Pt 6):607-608.
In the solid-state photodimerization of cinnamic acid polymorphs, can mechanical properties tell us whether Schmidt ‘minimal molecular movement’ or Kaupp ‘molecular migration’ is more important?
PMCID: PMC4645103  PMID: 26594366
photomechanical properties; solid-state reactions; crystal engineering; cinnamic acid; nanoindentation
5.  Protease inhibitor monotherapy for long-term management of HIV infection: a randomised, controlled, open-label, non-inferiority trial 
The Lancet. HIV  2015;2(10):e417-e426.
Standard-of-care antiretroviral therapy (ART) uses a combination of drugs deemed essential to minimise treatment failure and drug resistance. Protease inhibitors are potent, with a high genetic barrier to resistance, and have potential use as monotherapy after viral load suppression is achieved with combination treatment. We aimed to assess clinical risks and benefits of protease inhibitor monotherapy in long-term clinical use: in particular, the effect on drug resistance and future treatment options.
In this pragmatic, parallel-group, randomised, controlled, open-label, non-inferiority trial, we enrolled adults (≥18 years of age) positive for HIV attending 43 public sector treatment centres in the UK who had suppressed viral load (<50 copies per mL) for at least 24 weeks on combination ART with no change in the previous 12 weeks and a CD4 count of more than 100 cells per μL. Participants were randomly allocated (1:1) to maintain ongoing triple therapy (OT) or to switch to a strategy of physician-selected ritonavir-boosted protease inhibitor monotherapy (PI-mono); we recommended ritonavir (100 mg)-boosted darunavir (800 mg) once daily or ritonavir (100 mg)-boosted lopinavir (400 mg) twice daily, with prompt return to combination treatment if viral load rebounded. All treatments were oral. Randomisation was with permuted blocks of varying size and stratified by centre and baseline ART; we used a computer-generated, sequentially numbered randomisation list. The primary outcome was loss of future drug options, defined as new intermediate-level or high-level resistance to one or more drugs to which the patient's virus was deemed sensitive at trial entry (assessed at 3 years; non-inferiority margin of 10%). We estimated probability of rebound and resistance with Kaplan-Meier analysis. Analyses were by intention to treat. This trial is registered with the International Standard Randomised Controlled Trial Number registry, number ISRCTN04857074.
Between Nov 4, 2008, and July 28, 2010, we randomly allocated 587 participants to OT (291) or PI-mono (296). At 3 years, one or more future drug options had been lost in two participants (Kaplan-Meier estimate 0·7%) in the OT group and six (2·1%) in the PI-mono group: difference 1·4% (−0·4 to 3·4); non-inferiority shown. 49 (16·8%) participants in the OT group and 65 (22·0%) in the PI-mono group had grade 3 or 4 clinical adverse events (difference 5·1% [95% CI −1·3 to 11·5]; p=0·12); 45 (six treatment related) and 56 (three treatment related) had serious adverse events.
Protease inhibitor monotherapy, with regular viral load monitoring and prompt reintroduction of combination treatment for rebound, preserved future treatment options and did not change overall clinical outcomes or frequency of toxic effects. Protease inhibitor monotherapy is an acceptable alternative for long-term clinical management of HIV infection.
National Institute for Health Research.
PMCID: PMC4765553  PMID: 26423649
6.  National Outbreak of Type A Foodborne Botulism Associated With a Widely Distributed Commercially Canned Hot Dog Chili Sauce 
On 7 and 11 July 2007, health officials in Texas and Indiana, respectively, reported 4 possible cases of type A foodborne botulism to the US Centers for Disease Control and Prevention. Foodborne botulism is a rare and sometimes fatal illness caused by consuming foods containing botulinum neurotoxin.
Investigators reviewed patients’ medical charts and food histories. Clinical specimens and food samples were tested for botulinum toxin and neurotoxin-producing Clostridium species. Investigators conducted inspections of the cannery that produced the implicated product.
Eight confirmed outbreak associated cases were identified from Indiana (n = 2), Texas (n = 3), and Ohio (n = 3). Botulinum toxin type A was identified in leftover chili sauce consumed by the Indiana patients and 1 of the Ohio patients. Cannery inspectors found violations of federal canned-food regulations that could have led to survival of Clostridium botulinum spores during sterilization. The company recalled 39 million cans of chili. Following the outbreak, the US Food and Drug Administration inspected other canneries with similar canning systems and issued warnings to the industry about the danger of C. botulinum and the importance of compliance with canned food manufacturing regulations.
Commercially produced hot dog chili sauce caused these cases of type A botulism. This is the first US foodborne botulism outbreak involving a commercial cannery in >30 years. Sharing of epidemiologic and laboratory findings allowed for the rapid identification of implicated food items and swift removal of potentially deadly products from the market by US food regulatory authorities.
PMCID: PMC4538949  PMID: 23097586
botulism; commercial canning; outbreak; foodborne botulism
7.  Relationship between inflammatory and coagulation biomarkers and cardiac autonomic function in HIV-infected individuals 
Biomarkers in medicine  2014;8(9):1073-1083.
To examine the relationship between inflammatory and coagulation biomarkers and cardiac autonomic function (CAF) as measured by heart rate variability in persons with HIV.
Materials & methods
This analysis included 4073 HIV-infected persons from the Strategies for Management of Antiretroviral Therapy study. We examined the association between IL-6, high-sensitivity C-reactive protein (hsCRP) and d-dimer with heart rate variability measures (SDNN and rMSSD), both cross-sectionally and longitudinally.
Cross-sectional analysis revealed significant inverse associations between IL-6, hsCRP and d-dimer with SDNN and rMSSD (p < 0.01 for all comparisons). However, longitudinal analysis failed to show a significant association between baseline IL-6, hsCRP and d-dimer with change in CAF over time.
Cross-sectionally, higher levels of inflammatory and coagulation biomarkers were associated with lower levels of CAF in the Strategies for Management of Antiretroviral Therapy trial. Although deterioration in CAF was observed during followup, baseline levels of inflammatory and coagulation markers were not predictive of the decline in CAF over time.
PMCID: PMC4278423  PMID: 25402578
biomarkers; cardiac autonomic function; coagulation; d-dimer; heart rate variability; high-sensitivity C-reactive protein; HIV; inflammation; IL-6
8.  Hybrid Spreading Mechanisms and T Cell Activation Shape the Dynamics of HIV-1 Infection 
PLoS Computational Biology  2015;11(4):e1004179.
HIV-1 can disseminate between susceptible cells by two mechanisms: cell-free infection following fluid-phase diffusion of virions and by highly-efficient direct cell-to-cell transmission at immune cell contacts. The contribution of this hybrid spreading mechanism, which is also a characteristic of some important computer worm outbreaks, to HIV-1 progression in vivo remains unknown. Here we present a new mathematical model that explicitly incorporates the ability of HIV-1 to use hybrid spreading mechanisms and evaluate the consequences for HIV-1 pathogenenesis. The model captures the major phases of the HIV-1 infection course of a cohort of treatment naive patients and also accurately predicts the results of the Short Pulse Anti-Retroviral Therapy at Seroconversion (SPARTAC) trial. Using this model we find that hybrid spreading is critical to seed and establish infection, and that cell-to-cell spread and increased CD4+ T cell activation are important for HIV-1 progression. Notably, the model predicts that cell-to-cell spread becomes increasingly effective as infection progresses and thus may present a considerable treatment barrier. Deriving predictions of various treatments’ influence on HIV-1 progression highlights the importance of earlier intervention and suggests that treatments effectively targeting cell-to-cell HIV-1 spread can delay progression to AIDS. This study suggests that hybrid spreading is a fundamental feature of HIV infection, and provides the mathematical framework incorporating this feature with which to evaluate future therapeutic strategies.
Author Summary
The ability to spread using more than once mechanism, named hybrid spreading, is a ubiquitous feature of many real world epidemics including HIV and Hepatitis C virus infection in vivo, and computer worms spreading on the Internet. Hybrid spreading of HIV is well documented experimentally but its importance to HIV progression has been unclear. In this paper, we introduce a mathematical model of HIV dynamics that explicitly incorporates hybrid spreading. The model output shows excellent agreement to two sets of clinical data from a treatment naive cohort and from the Short Pulse Anti-Retroviral Therapy at Seroconversion trial. The model demonstrates that hybrid spreading is an essential feature of HIV progression, a result which has significant implications for future therapeutic strategies against HIV.
PMCID: PMC4383537  PMID: 25837979
9.  Factors Associated with D-Dimer Levels in HIV-Infected Individuals 
PLoS ONE  2014;9(3):e90978.
Higher plasma D-dimer levels are strong predictors of mortality in HIV+ individuals. The factors associated with D-dimer levels during HIV infection, however, remain poorly understood.
In this cross-sectional study, participants in three randomized controlled trials with measured D-dimer levels were included (N = 9,848). Factors associated with D-dimer were identified by linear regression. Covariates investigated were: age, gender, race, body mass index, nadir and baseline CD4+ count, plasma HIV RNA levels, markers of inflammation (C-reactive protein [CRP], interleukin-6 [IL-6]), antiretroviral therapy (ART) use, ART regimens, co-morbidities (hepatitis B/C, diabetes mellitus, prior cardiovascular disease), smoking, renal function (estimated glomerular filtration rate [eGFR] and cystatin C) and cholesterol.
Women from all age groups had higher D-dimer levels than men, though a steeper increase of D-dimer with age occurred in men. Hepatitis B/C co-infection was the only co-morbidity associated with higher D-dimer levels. In this subgroup, the degree of hepatic fibrosis, as demonstrated by higher hyaluronic acid levels, but not viral load of hepatitis viruses, was positively correlated with D-dimer. Other factors independently associated with higher D-dimer levels were black race, higher plasma HIV RNA levels, being off ART at baseline, and increased levels of CRP, IL-6 and cystatin C. In contrast, higher baseline CD4+ counts and higher high-density lipoprotein cholesterol were negatively correlated with D-dimer levels.
D-dimer levels increase with age in HIV+ men, but are already elevated in women at an early age due to reasons other than a higher burden of concomitant diseases. In hepatitis B/C co-infected individuals, hepatic fibrosis, but not hepatitis viral load, was associated with higher D-dimer levels.
PMCID: PMC3953205  PMID: 24626096
10.  Friends or Foes? Relational Dissonance and Adolescent Psychological Wellbeing 
PLoS ONE  2014;9(2):e83388.
The interaction of positive and negative relationships (i.e. I like you, but you dislike me – referred to as relational dissonance) is an underexplored phenomenon. Further, it is often only poor (or negative) mental health that is examined in relation to social networks, with little regard for positive psychological wellbeing. Finally, these issues are compounded by methodological constraints. This study explores a new concept of relational dissonance alongside mutual antipathies and friendships and their association with mental health using multivariate exponential random graph models with an Australian sample of secondary school students. Results show male students with relationally dissonant ties have lower positive mental health measures. Girls with relationally dissonant ties have lower depressed mood, but those girls being targeted by negative ties are more likely to have depressed mood. These findings have implications for the development of interventions focused on promoting adolescent wellbeing and consideration of the appropriate measurement of wellbeing and mental illness.
PMCID: PMC3911895  PMID: 24498257
11.  Effect of DISC1 on the P300 Waveform in Psychosis 
Schizophrenia Bulletin  2011;39(1):161-167.
Introduction: Abnormalities in the neurophysiological measures P300 amplitude and latency constitute endophenotypes for psychosis. Disrupted-in-Schizophrenia-1 (DISC1) has been proposed as a promising susceptibility gene for schizophrenia, and a previous study has suggested that it is associated with P300 deficits in schizophrenia. Methods: We examined the role of variation in DISC1 polymorphisms on the P300 endophenotype in a large sample of patients with schizophrenia or psychotic bipolar disorder (n = 149), their unaffected relatives (n = 130), and unrelated healthy controls (n = 208) using linear regression and haplotype analysis. Results: Significant associations between P300 amplitude and latency and DISC1 polymorphisms/haplotypes were found. Those homozygous for the A allele of single-nucleotide polymorphism (SNP) rs821597 displayed significantly reduced P300 amplitudes in comparison with homozygous for the G allele (P = .009) and the heterozygous group (P = .018). Haplotype analysis showed a significant association for DISC1 haplotypes (rs3738401|rs6675281|rs821597|rs821616|rs967244|rs980989) and P300 latency. Haplotype GCGTCG and ACGTTT were associated with shorter latencies. Discussion: The P300 waveform appears to be modulated by variation in individual SNPs and haplotypes of DISC1. Because DISC1 is involved in neurodevelopment, one hypothesis is that disruption in neural connectivity impairs cognitive processes illustrated by P300 deficits observed in this sample.
PMCID: PMC3523903  PMID: 21878470
psychosis; schizophrenia; bipolar disorder; EEG; ERP; P300; DISC1; endophenotype; neurophysiology; family study; haplotype analysis; biomarker
12.  Computationally efficient modeling of proprioceptive signals in the upper limb for prostheses: a simulation study 
Accurate models of proprioceptive neural patterns could 1 day play an important role in the creation of an intuitive proprioceptive neural prosthesis for amputees. This paper looks at combining efficient implementations of biomechanical and proprioceptor models in order to generate signals that mimic human muscular proprioceptive patterns for future experimental work in prosthesis feedback. A neuro-musculoskeletal model of the upper limb with 7 degrees of freedom and 17 muscles is presented and generates real time estimates of muscle spindle and Golgi Tendon Organ neural firing patterns. Unlike previous neuro-musculoskeletal models, muscle activation and excitation levels are unknowns in this application and an inverse dynamics tool (static optimization) is integrated to estimate these variables. A proprioceptive prosthesis will need to be portable and this is incompatible with the computationally demanding nature of standard biomechanical and proprioceptor modeling. This paper uses and proposes a number of approximations and optimizations to make real time operation on portable hardware feasible. Finally technical obstacles to mimicking natural feedback for an intuitive proprioceptive prosthesis, as well as issues and limitations with existing models, are identified and discussed.
PMCID: PMC4069835  PMID: 25009463
proprioceptive feedback; neuroprosthesis; neuromusculoskeletal model; upper limb; biomechanics; muscle spindles; golgi tendon organ; static optimization
13.  Neuromodulation: present and emerging methods 
Neuromodulation has wide ranging potential applications in replacing impaired neural function (prosthetics), as a novel form of medical treatment (therapy), and as a tool for investigating neurons and neural function (research). Voltage and current controlled electrical neural stimulation (ENS) are methods that have already been widely applied in both neuroscience and clinical practice for neuroprosthetics. However, there are numerous alternative methods of stimulating or inhibiting neurons. This paper reviews the state-of-the-art in ENS as well as alternative neuromodulation techniques—presenting the operational concepts, technical implementation and limitations—in order to inform system design choices.
PMCID: PMC4097946  PMID: 25076887
neuromodulation; neural modulation; neurostimulation; neural stimulation; neuroprosthetics; neural prosthesis
14.  Relative resistance of HIV-1 founder viruses to control by interferon-alpha 
Retrovirology  2013;10:146.
Following mucosal human immunodeficiency virus type 1 (HIV-1) transmission, type 1 interferons (IFNs) are rapidly induced at sites of initial virus replication in the mucosa and draining lymph nodes. However, the role played by IFN-stimulated antiviral activity in restricting HIV-1 replication during the initial stages of infection is not clear. We hypothesized that if type 1 IFNs exert selective pressure on HIV-1 replication in the earliest stages of infection, the founder viruses that succeed in establishing systemic infection would be more IFN-resistant than viruses replicating during chronic infection, when type 1 IFNs are produced at much lower levels. To address this hypothesis, the relative resistance of virus isolates derived from HIV-1-infected individuals during acute and chronic infection to control by type 1 IFNs was analysed.
The replication of plasma virus isolates generated from subjects acutely infected with HIV-1 and molecularly cloned founder HIV-1 strains could be reduced but not fully suppressed by type 1 IFNs in vitro. The mean IC50 value for IFNα2 (22 U/ml) was lower than that for IFNβ (346 U/ml), although at maximally-inhibitory concentrations both IFN subtypes inhibited virus replication to similar extents. Individual virus isolates exhibited differential susceptibility to inhibition by IFNα2 and IFNβ, likely reflecting variation in resistance to differentially up-regulated IFN-stimulated genes. Virus isolates from subjects acutely infected with HIV-1 were significantly more resistant to in vitro control by IFNα than virus isolates generated from the same individuals during chronic, asymptomatic infection. Viral IFN resistance declined rapidly after the acute phase of infection: in five subjects, viruses derived from six-month consensus molecular clones were significantly more sensitive to the antiviral effects of IFNs than the corresponding founder viruses.
The establishment of systemic HIV-1 infection by relatively IFNα-resistant founder viruses lends strong support to the hypothesis that IFNα plays an important role in the control of HIV-1 replication during the earliest stages of infection, prior to systemic viral spread. These findings suggest that it may be possible to harness the antiviral activity of type 1 IFNs in prophylactic and potentially also therapeutic strategies to combat HIV-1 infection.
PMCID: PMC3907080  PMID: 24299076
Human immunodeficiency virus type 1; Type 1 interferon; Viral inhibition; Founder virus; Acute infection
15.  Effects of Hydroxychloroquine on Immune Activation and Disease Progression Among HIV-Infected Patients Not Receiving Antiretroviral Therapy A Randomized Controlled Trial 
JAMA : the journal of the American Medical Association  2012;308(4):10.1001/jama.2012.6936.
Therapies to decrease immune activation might be of benefit in slowing HIV disease progression.
To determine whether hydroxychloroquine decreases immune activation and slows CD4 cell decline.
Design, Setting, and Patients
Randomized, double-blind, placebo-controlled trial performed at 10 HIV outpatient clinics in the United Kingdom between June 2008 and February 2011. The 83 patients enrolled had asymptomatic HIV infection, were not taking antiretroviral therapy, and had CD4 cell counts greater than 400 cells/μL.
Hydroxychloroquine, 400 mg, or matching placebo once daily for 48 weeks.
Main Outcome Measures
The primary outcome measure was change in the proportion of activated CD8 cells (measured by the expression of CD38 and HLA-DR surface markers), with CD4 cell count and HIV viral load as secondary outcomes. Analysis was by intention to treat using mixed linear models.
There was no significant difference in CD8 cell activation between the 2 groups (−4.8% and −4.2% in the hydroxychloroquine and placebo groups, respectively, at week 48; difference, −0.6%; 95% CI, −4.8% to 3.6%; P=.80). Decline in CD4 cell count was greater in the hydroxychloroquine than placebo group (−85 cells/μL vs −23 cells/μL at week 48; difference, −62 cells/μL; 95% CI, −115 to −8; P=.03). Viral load increased in the hydroxychloroquine group compared with placebo (0.61 log10 copies/mL vs 0.23 log10 copies/mL at week 48; difference, 0.38 log10 copies/mL; 95% CI, 0.13 to 0.63; P=.003). Antiretroviral therapy was started in 9 patients in the hydroxychloroquine group and 1 in the placebo group. Trial medication was well tolerated, but more patients reported influenza-like illness in the hydroxychloroquine group compared with the placebo group (29% vs 10%; P=.03).
Among HIV-infected patients not taking antiretroviral therapy, the use of hydroxychloroquine compared with placebo did not reduce CD8 cell activation but did result in a greater decline in CD4 cell count and increased viral replication.
Trial Registration Identifier: ISRCTN30019040
PMCID: PMC3821003  PMID: 22820788
17.  Persistence of HIV-1 Transmitted Drug Resistance Mutations 
The Journal of Infectious Diseases  2013;208(9):1459-1463.
There are few data on the persistence of individual human immunodeficiency virus type 1 (HIV-1) transmitted drug resistance (TDR) mutations in the absence of selective drug pressure. We studied 313 patients in whom TDR mutations were detected at their first resistance test and who had a subsequent test performed while ART-naive. The rate at which mutations became undetectable was estimated using exponential regression accounting for interval censoring. Most thymidine analogue mutations (TAMs) and T215 revertants (but not T215F/Y) were found to be highly stable, with NNRTI and PI mutations being relatively less persistent. Our estimates are important for informing HIV transmission models.
PMCID: PMC3789571  PMID: 23904291
persistence; transmitted; HIV-1; resistance; mutations
18.  Low frequency of genotypic resistance in HIV-1-infected patients failing an atazanavir-containing regimen: a clinical cohort study 
Dolling, David I. | Dunn, David T. | Sutherland, Katherine A. | Pillay, Deenan | Mbisa, Jean L. | Parry, Chris M. | Post, Frank A. | Sabin, Caroline A. | Cane, Patricia A. | Aitken, Celia | Asboe, David | Webster, Daniel | Cane, Patricia | Castro, Hannah | Dunn, David | Dolling, David | Chadwick, David | Churchill, Duncan | Clark, Duncan | Collins, Simon | Delpech, Valerie | Geretti, Anna Maria | Goldberg, David | Hale, Antony | Hué, Stéphane | Kaye, Steve | Kellam, Paul | Lazarus, Linda | Leigh-Brown, Andrew | Mackie, Nicola | Orkin, Chloe | Rice, Philip | Pillay, Deenan | Phillips, Andrew | Sabin, Caroline | Smit, Erasmus | Templeton, Kate | Tilston, Peter | Tong, William | Williams, Ian | Zhang, Hongyi | Zuckerman, Mark | Greatorex, Jane | Wildfire, Adrian | O'Shea, Siobhan | Mullen, Jane | Mbisa, Tamyo | Cox, Alison | Tandy, Richard | Hale, Tony | Fawcett, Tracy | Hopkins, Mark | Ashton, Lynn | Booth, Claire | Garcia-Diaz, Ana | Shepherd, Jill | Schmid, Matthias L. | Payne, Brendan | Hay, Phillip | Rice, Phillip | Paynter, Mary | Bibby, David | Kirk, Stuart | MacLean, Alasdair | Gunson, Rory | Coughlin, Kate | Fearnhill, Esther | Fradette, Lorraine | Porter, Kholoud | Ainsworth, Jonathan | Anderson, Jane | Babiker, Abdel | Fisher, Martin | Gazzard, Brian | Gilson, Richard | Gompels, Mark | Hill, Teresa | Johnson, Margaret | Kegg, Stephen | Leen, Clifford | Nelson, Mark | Palfreeman, Adrian | Post, Frank | Sachikonye, Memory | Schwenk, Achim | Walsh, John | Huntington, Susie | Jose, Sophie | Thornton, Alicia | Glabay, Adam | Orkin, C. | Garrett, N. | Lynch, J. | Hand, J. | de Souza, C. | Fisher, M. | Perry, N. | Tilbury, S. | Gazzard, B. | Nelson, M. | Waxman, M. | Asboe, D. | Mandalia, S. | Delpech, V. | Anderson, J. | Munshi, S. | Korat, H. | Welch, J. | Poulton, M. | MacDonald, C. | Gleisner, Z. | Campbell, L. | Gilson, R. | Brima, N. | Williams, I. | Schwenk, A. | Ainsworth, J. | Wood, C. | Miller, S. | Johnson, M. | Youle, M. | Lampe, F. | Smith, C. | Grabowska, H. | Chaloner, C. | Puradiredja, D. | Walsh, J. | Weber, J. | Ramzan, F. | Mackie, N. | Winston, A. | Leen, C. | Wilson, A. | Allan, S. | Palfreeman, A. | Moore, A. | Wakeman, K.
Journal of Antimicrobial Chemotherapy  2013;68(10):2339-2343.
To determine protease mutations that develop at viral failure for protease inhibitor (PI)-naive patients on a regimen containing the PI atazanavir.
Resistance tests on patients failing atazanavir, conducted as part of routine clinical care in a multicentre observational study, were randomly matched by subtype to resistance tests from PI-naive controls to account for natural polymorphisms. Mutations from the consensus B sequence across the protease region were analysed for association and defined using the IAS-USA 2011 classification list.
Four hundred and five of 2528 (16%) patients failed therapy containing atazanavir as a first PI over a median (IQR) follow-up of 1.76 (0.84–3.15) years and 322 resistance tests were available for analysis. Recognized major atazanavir mutations were found in six atazanavir-experienced patients (P < 0.001), including I50L and N88S. The minor mutations most strongly associated with atazanavir experience were M36I, M46I, F53L, A71V, V82T and I85V (P < 0.05). Multiple novel mutations, I15S, L19T, K43T, L63P/V, K70Q, V77I and L89I/T/V, were also associated with atazanavir experience.
Viral failure on atazanavir-containing regimens was not common and major resistance mutations were rare, suggesting that adherence may be a major contributor to viral failure. Novel mutations were described that have not been previously documented.
PMCID: PMC3772741  PMID: 23711895
HIV; drug resistance mutations; naive patients; protease inhibitors; virological failure
19.  Formation of the world's largest REE deposit through protracted fluxing of carbonatite by subduction-derived fluids 
Scientific Reports  2013;3:1776.
Rare Earth Elements (REE) are essential to modern society but the origins of many large REE deposits remain unclear. The U-Th-Pb ages, chemical compositions and C, O and Mg isotopic compositions of Bayan Obo, the world's largest REE deposit, indicate a protracted mineralisation history with unusual chemical and isotopic features. Coexisting calcite and dolomite are in O isotope disequilibrium; some calcitic carbonatite samples show highly varied δ26Mg which increases with increasing Si and Mg; and ankerite crystals show decreases in Fe and REE from rim to centre, with highly varied REE patterns. These and many other observations are consistent with an unusual mineralisation process not previously considered; protracted fluxing of calcitic carbonatite by subduction-released high-Si fluids during the closure of the Palaeo-Asian Ocean. The fluids leached Fe and Mg from the mantle wedge and scavenged REE, Nb and Th from carbonatite, forming the deposit through metasomatism of overlying sedimentary carbonate.
PMCID: PMC3646268
20.  Outbreak of Shiga Toxin-Producing Escherichia coli (STEC) O157:H7 Associated with Romaine Lettuce Consumption, 2011 
PLoS ONE  2013;8(2):e55300.
Shiga toxin-producing Escherichia coli (STEC) O157:H7 is the causal agent for more than 96,000 cases of diarrheal illness and 3,200 infection-attributable hospitalizations annually in the United States.
Materials and Methods
We defined a confirmed case as a compatible illness in a person with the outbreak strain during 10/07/2011-11/30/2011. Investigation included hypothesis generation, a case-control study utilizing geographically-matched controls, and a case series investigation. Environmental inspections and tracebacks were conducted.
We identified 58 cases in 10 states; 67% were hospitalized and 6.4% developed hemolytic uremic syndrome. Any romaine consumption was significantly associated with illness (matched Odds Ratio (mOR) = 10.0, 95% Confidence Interval (CI) = 2.1–97.0). Grocery Store Chain A salad bar was significantly associated with illness (mOR = 18.9, 95% CI = 4.5–176.8). Two separate traceback investigations for romaine lettuce converged on Farm A. Case series results indicate that cases (64.9%) were more likely than the FoodNet population (47%) to eat romaine lettuce (p-value = 0.013); 61.3% of cases reported consuming romaine lettuce from the Grocery Store Chain A salad bar.
This multistate outbreak of STEC O157:H7 infections was associated with consumption of romaine lettuce. Traceback analysis determined that a single common lot of romaine lettuce harvested from Farm A was used to supply Grocery Store Chain A and a university campus linked to a case with the outbreak strain. An investigation at Farm A did not identify the source of contamination. Improved ability to trace produce from the growing fields to the point of consumption will allow more timely prevention and control measures to be implemented.
PMCID: PMC3563629  PMID: 23390525
21.  Lower Healthcare Costs Associated with the Use of a Single-Pill ARV Regimen in the UK, 2004–2008 
PLoS ONE  2012;7(10):e47376.
Investigate the cost and effects of a single-pill versus two- or three pill first-line antiretroviral combinations in reducing viral load, increasing CD4 counts, and first-line failure rate associated with respective regimens at 6 and 12 months.
Patients on first-line TDF+3TC+EFV, TDF+FTC+EFV, Truvada®+EFV or Atripla® between 1996–2008 were identified and viral load and CD4 counts measured at baseline, six and twelve months respectively. Factors that independently predicted treatment failure at six and twelve months were derived using multivariate Cox's proportional hazard regression analyses. Use and cost of hospital services were calculated at six and twelve months respectively.
All regimens reduced viral load to below the limit of detection and CD4 counts increased to similar levels at six and twelve months for all treatment regimens. No statistically significant differences were observed for rate of treatment failure at six and twelve months. People on Atripla® generated lower healthcare costs for non-AIDS patients at £5,340 (£5,254 to £5,426) per patient-semester and £9,821 (£9,719 to £9,924) per patient-year that was £1,344 (95%CI £1,222 to £1,465) less per patient-semester and £1,954 (95%CI £1,801 to £2,107) less per patient-year compared with Truvada®+EFV; healthcare costs for AIDS patients were similar across all regimens.
The single pill regimen is as effective as the two- and three-pill regimens of the same drugs, but if started as first-line induction therapy there would be a 20% savings on healthcare costs at six and 17% of costs at twelve months compared with Truvada®+EFV, that generated the next lowest costs.
PMCID: PMC3484120  PMID: 23118869
22.  Integrating a pharmacist into the general practice environment: opinions of pharmacist’s, general practitioner’s, health care consumer’s, and practice manager’s 
Pharmacists are viewed as highly trained yet underutilised and there is growing support to extend the role of the pharmacist within the primary health care sector. The integration of a pharmacist into a general practice medical centre is not a new concept however is a novel approach in Australia and evidence supporting this role is currently limited. This study aimed to describe the opinions of local stakeholders in South-East Queensland on the integration of a pharmacist into the Australian general practice environment.
A sample of general practitioners, health care consumers, pharmacists and practice managers in South-East Queensland were invited to participate in focus groups or semi-structured interviews. Seeding questions common to all sessions were used to facilitate discussion. Sessions were audio recorded and transcribed verbatim. Leximancer software was used to qualitatively analyse responses.
A total of 58 participants took part in five focus groups and eighteen semi-structured interviews. Concepts relating to six themes based on the seeding questions were identified. These included positively viewed roles such as medication reviews and prescribing, negatively viewed roles such as dispensing and diagnosing, barriers to pharmacist integration such as medical culture and remuneration, facilitators to pharmacist integration such as remuneration and training, benefits of integration such as access to the patient’s medical file, and potential funding models.
These findings and future research may aid the development of a new model of integrated primary health care services involving pharmacist practitioners.
PMCID: PMC3444319  PMID: 22852792
23.  Authors' response 
PMCID: PMC3123477
24.  HIV: low prevalence is no excuse for not testing 
PMCID: PMC3063012  PMID: 21439181
25.  The Cost-Effectiveness of Early Access to HIV Services and Starting cART in the UK 1996–2008 
PLoS ONE  2011;6(12):e27830.
To calculate use, cost and cost-effectiveness of people living with HIV (PLHIV) starting routine treatment and care before starting combination antiretroviral therapy (cART) and PLHIV starting first-line 2NRTIs+NNRTI or 2NRTIs+PIboosted, comparing PLHIV with CD4≤200 cells/mm3 and CD4>200 cells/mm3. Few studies have calculated the use, cost and cost-effectiveness of routine treatment and care before starting cART and starting cART above and below CD4 200 cells/mm3.
Use, costs and cost-effectiveness were calculated for PLHIV in routine pre-cART and starting first-line cART, comparing CD4≤200 cells/mm3 with CD4>200 cells/mm3 (2008 UK prices).
cART naïve patients CD4≤200 cells/mm3 had an annual cost of £6,407 (95%CI £6,382 to £6,425) PPY compared with £2,758 (95%CI £2,752 to £2,761) PPY for those with CD4>200 cells/mm3; cost per life year gained of pre-cART treatment and care for those with CD4>200 cells/mm3 was £1,776 (cost-saving to £2,752). Annual cost for starting 2NRTIs+NNRTI or 2NRTIs+PIboosted with CD4≤200 cells/mm3 was £12,812 (95%CI £12,685–£12,937) compared with £10,478 (95%CI £10,376–£10,581) for PLHIV with CD4>200 cells/mm3. Cost per additional life-year gained on first-line therapy for those with CD4>200 cells/mm3 was £4639 (£3,967 to £2,960).
PLHIV starting to use HIV services before CD4≤200 cells/mm3 is cost-effective and enables them to be monitored so they start cART with a CD4>200 cells/mm3, which results in better outcomes and is cost-effective. However, 25% of PLHIV accessing services continue to present with CD4≤200 cells/mm3. This highlights the need to investigate the cost-effectiveness of testing and early treatment programs for key populations in the UK.
PMCID: PMC3237423  PMID: 22194795

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