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1.  Determination of the mental foramen position in dental radiographs in 18–30 year olds 
Dentomaxillofacial Radiology  2015;45(1):20150195.
To determine the radiographic position and reliability of assessing mental foramen (MF) position in relation to premolar crowns in an 18- to 30-year-old UK-based population.
Following ethical approval and a power calculation, the position of the MF was recorded in relation to premolar crowns and apices in 100 dental panoramic tomographs. Positions were assessed by three senior clinicians independently, then by consensus. Data were analysed using descriptive statistics, χ2 and Fleiss' and Cohen's kappa.
Reliability data showed only fair to moderate agreement on independent scoring. Substantial to almost perfect agreement was achieved by consensus, demonstrating the most common position for the MF to be between the first and second premolar teeth when using both premolar crowns (51%) and apices (76%) as reference points. There was a significant difference in the position of the foramen between the left and right sides (p < 0.05), with only 62% of cases showing symmetry.
The most common position for the MF is between the first and second premolar teeth; however, anatomical variation is seen. Use of pre-operative radiographs to relate the position of the MF to premolar crowns may not be reliable.
PMCID: PMC5083892  PMID: 26371076
dental radiography; reproducibility of results; anatomy
2.  Epidemiological Evidence for Cardiovascular Disease in HIV-Infected Patients and Relationship to Highly Active Antiretroviral Therapy 
Circulation  2008;118(2):e29-e35.
PMCID: PMC5153327  PMID: 18566319 CAMSID: cams1226
AHA Conference Proceedings; AIDS; HIV; myocardial infarction; antiretroviral therapy; protease inhibitors
3.  The magnitude and temporal changes of response in the placebo arm of surgical randomized controlled trials: a systematic review and meta-analysis 
Trials  2016;17:589.
Understanding changes in the placebo arm is essential for correct design and interpretation of randomized controlled trials (RCTs). It is assumed that placebo response, defined as the total improvement in the placebo arm of surgical trials, is large; however, its precise magnitude and properties remain to be characterized. To the best of our knowledge, the temporal changes in the placebo arm have not been investigated. The aim of this paper was to determine, in surgical RCTs, the magnitude of placebo response and how it is affected by duration of follow-up.
The databases of MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials and were searched from their inception to 20 October 2015 for studies comparing the efficacy of a surgical intervention with placebo. Inclusion was not limited to any particular condition, intervention, outcome or patient population. The magnitude of placebo response was estimated using standardized mean differences (SMDs). Study estimates were pooled using random effects meta-analysis. Potential sources of heterogeneity were evaluated using stratification and meta-regression.
Database searches returned 88 studies, but for 41 studies SMDs could not be calculated, leaving 47 trials (involving 1744 participants) eligible for inclusion. There were no temporal changes in placebo response within the analysed trials. Meta-regression analysis showed that duration of follow-up did not have a significant effect on the magnitude of the placebo response and that the strongest predictor of placebo response was subjectivity of the outcome. The pooled effect in the placebo arm of studies with subjective outcomes was large (0.64, 95% CI 0.5 to 0.8) and remained significantly different from zero regardless of the duration of follow-up, whereas for objective outcomes, the effect was small (0.11, 95% CI 0.04 to 0.26) or non-significant across all time points.
This is the first study to investigate the temporal changes of placebo response in surgical trials and the first to investigate the sources of heterogeneity of placebo response. Placebo response in surgical trials was large for subjective outcomes, persisting as a time-invariant effect throughout blinded follow-up. Therefore, placebo response cannot be minimized in these types of outcomes through their appraisal at alternative time points. The analyses suggest that objective outcomes may be preferable as trial end-points. Where subjective outcomes are of primary interest, a placebo arm is necessary to control for placebo response.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-016-1720-7) contains supplementary material, which is available to authorized users.
PMCID: PMC5154040  PMID: 27955685
Surgery; Placebos; Randomized controlled trials; Systematic review; Meta-analysis
4.  Study protocol: a dose-escalating, phase-2 study of oral lisdexamfetamine in adults with methamphetamine dependence 
BMC Psychiatry  2016;16:428.
The treatment of methamphetamine dependence is a continuing global health problem. Agonist type pharmacotherapies have been used successfully to treat opioid and nicotine dependence and are being studied for the treatment of methamphetamine dependence. One potential candidate is lisdexamfetamine, a pro-drug for dexamphetamine, which has a longer lasting therapeutic action with a lowered abuse potential. The purpose of this study is to determine the safety of lisdexamfetamine in this population at doses higher than those currently approved for attention deficit hyperactivity disorder or binge eating disorder.
This is a phase 2 dose escalation study of lisdexamfetamine for the treatment of methamphetamine dependence. Twenty individuals seeking treatment for methamphetamine dependence will be recruited at two Australian drug and alcohol services. All participants will undergo a single-blinded ascending-descending dose regime of 100 to 250 mg lisdexamfetamine, dispensed daily on site, over an 8-week period. Participants will be offered counselling as standard care. For the primary objectives the outcome variables will be adverse events monitoring, drug tolerability and regimen completion. Secondary outcomes will be changes in methamphetamine use, craving, withdrawal, severity of dependence, risk behaviour and other substance use. Medication acceptability, potential for non-prescription use, adherence and changes in neurocognition will also be measured.
Determining the safety of lisdexamfetamine will enable further research to develop pharmacotherapies for the treatment of methamphetamine dependence.
Trial registration
Australian and New Zealand Clinical Trials Registry ACTRN12615000391572 Registered 28th April 2015.
PMCID: PMC5134059  PMID: 27905916
Methamphetamine; Study protocol; Lisdexamfetamine; Pharmacotherapy; Dose-finding; Stimulant use disorder
5.  A comparison of the Oxford shoulder score and shoulder pain and disability index: factor structure in the context of a large randomized controlled trial 
To explore and compare the factor structure of the 12-item Oxford shoulder score (OSS) and 13-item shoulder pain and disability index (SPADI).
Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) of data from 660 patients attending 46 hospitals in the UK. Complete OSS and SPADI data were available for 648 (98.2%) and 628 (95.2%) participants, respectively.
For both instruments, either one or two factors were indicated, depending on the extraction method. On EFA, most OSS items loaded saliently on either of two “Pain” (4 items) and “Function” (8 items) factors, although some items cross-loaded. Cronbach’s alphas were 0.75, 0.90, and 0.91 for “Pain” and “Function” subscales, and all 12 OSS items, respectively. CFA suggested marginally better fit for two factors, with neither one- nor two-factor models rejected. EFA indicated two factors for the SPADI, with three of the eight “Disability” items contributing to an 8-item “Pain factor”, with 2 items within the 5-item “Disability factor” cross-loading. Cronbach’s alpha was 0.87 and 0.93 for the original 5- and 8-item pain and disability scales; 0.94 for all 13 SPADI items, respectively. CFA suggested marginally better fit for the two-factor (original conceptualization) model of the SPADI, with neither one- nor two-factor models rejected.
EFA and CFA demonstrated that, in addition to single summary scales usage, separate information on pain and self-reported disability/function can be extracted in a meaningful way, as subscales, from both the OSS and the SPADI. This information can help researchers in choosing primary study endpoints appropriately.
PMCID: PMC5123655  PMID: 27920590
shoulder; Oxford shoulder score; shoulder pain and disability index; patient-reported outcome measures; factor analysis
6.  Profibrotic mediators in tendon disease: a systematic review 
Tendon disease is characterized by the development of fibrosis. Transforming growth factor beta (TGF-β), bone morphogenic proteins (BMPs) and connective tissue growth factor (CTGF) are key mediators in the pathogenesis of fibrotic disorders. The aim of this systematic review was to investigate the evidence for the expression of TGF-β, BMPs and CTGF along tendon disease progression and the response of tendon cells to these growth factors accordingly.
We conducted a systematic screen of the scientific literature using the Medline database. The search terms used were “tendon AND TGF-β,” “tendon AND BMP” or “tendon AND CTGF.” Studies of human samples, animal tendon injury and overuse models were included.
Thirty-three studies were included. In eight studies the expression of TGF-β, BMPs or CTGF was dysregulated in chronic tendinopathy and tendon tear patient tissues in comparison with healthy control tissues. The expression of TGF-β, BMPs and CTGF was increased and showed temporal changes in expression in tendon tissues from animal injury or overuse models compared with the healthy control (23 studies), but the pattern of upregulation was inconsistent between growth factors and also the type of animal model. No study investigated the differences in the effect of TGF-β, BMPs or CTGF treatment between patient-derived cells from healthy and diseased tendon tissues. Tendon cells derived from animal models of tendon injury showed increased expression of extracellular matrix protein genes and increased cell signaling response to TGF-β and BMP treatments compared with the control cells (two studies).
The expression of TGF-β, BMPs and CTGF in tendon tissues is altered temporally during healing in animal models of tendon injury or overuse, but the transition during the development of human tendon disease is currently unknown. Findings from this systematic review suggest a potential and compelling role for TGF-β, BMPs and CTGF in tendon disease; however, there is a paucity of studies analyzing their expression and stimulated cellular response in well-phenotyped human samples. Future work should investigate the dynamic expression of these fibrotic growth factors and their interaction with tendon cells using patient samples at different stages of human tendon disease.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-1165-0) contains supplementary material, which is available to authorized users.
PMCID: PMC5116130  PMID: 27863509
Tendon; Tendinopathy; Tendon tear; Fibrosis; Transforming growth factor beta; Bone morphogenic protein; Connective tissue growth factor
7.  An Investigation of Care-Based vs. Rule-Based Morality in Frontotemporal Dementia, Alzheimer’s Disease, and Healthy Controls 
Neuropsychologia  2015;78:73-79.
Behavioral changes in dementia, especially behavioral variant frontotemporal dementia (bvFTD), may result in alterations in moral reasoning. Investigators have not clarified whether these alterations reflect differential impairment of care-based vs. rule-based moral behavior. This study investigated 18 bvFTD patients, 22 early onset Alzheimer’s disease (eAD) patients, and 20 healthy age-matched controls on care-based and rule-based items from the Moral Behavioral Inventory and the Social Norms Questionnaire, neuropsychological measures, and magnetic resonance imaging (MRI) regions of interest. There were significant group differences with the bvFTD patients rating care-based morality transgressions less severely than the eAD group and rule-based moral behavioral transgressions more severely than controls. Across groups, higher care-based morality ratings correlated with phonemic fluency on neuropsychological tests, whereas higher rule-based morality ratings correlated with increased difficulty set-shifting and learning new rules to tasks. On neuroimaging, severe care-based reasoning correlated with cortical volume in right anterior temporal lobe, and rule-based reasoning correlated with decreased cortical volume in the right orbitofrontal cortex. Together, these findings suggest that frontotemporal disease decreases care-based morality and facilitates rule-based morality possibly from disturbed contextual abstraction and set-shifting. Future research can examine whether frontal lobe disorders and bvFTD result in a shift from empathic morality to the strong adherence to conventional rules.
PMCID: PMC4630103  PMID: 26432341
morality; dementia; brain; neuropsychology; neuroimaging; frontotemporal
8.  Maternal gestational vitamin D supplementation and offspring bone health: a multicentre randomised, double-blind, placebo-controlled trial (MAVIDOS) 
Maternal vitamin D status has been associated with lower bone mass of the offspring in many, but not all, observational studies. However, proof that maternal vitamin D repletion during pregnancy improves offspring bone mass is lacking.
Between 06/10/2008 and 11/02/2014, we randomly assigned pregnant women with a serum 25-hydroxyvitamin D [25(OH)D] 25-100nmol/l at 12 weeks’ gestation to either 1000IU/day cholecalciferol or matched placebo from 14 weeks’ gestation until delivery. Serum 25(OH)D was measured at 14 and 34 weeks’ gestation. Neonatal whole body bone mineral, assessed within 2 weeks after birth (n=665) by dual-energy X-ray absorptiometry (DXA), was the primary outcome. Secondary pre-specified analyses explored interactions with study centre, maternal ethnicity, parity, compliance, protocol completion, baseline BMI, baseline 25(OH)D and change in 25(OH)D from 14 to 34 weeks; and offspring sex and season of birth.
We found no difference in neonatal whole body bone mineral content (BMC) of infants born to mothers randomised to 1000IU/day cholecalciferol compared with infants born to mothers randomised to placebo [61.6g (95%CI: 60.3, 62.8g) vs 60.5g (95%CI: 59.3, 61.7g) respectively, p=0.21].
Supplementation of mothers with 1000IU/day cholecalciferol during pregnancy did not lead to increased offspring whole body BMC compared with placebo.
PMCID: PMC4843969  PMID: 26944421
Vitamin D; cholecalciferol; supplementation; trial; osteoporosis; epidemiology; DXA; pregnancy; neonate
9.  Determinants of the Maternal 25-Hydroxyvitamin D Response to Vitamin D Supplementation During Pregnancy 
Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response.
We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol.
Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy.
Hospital antenatal clinics.
A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks.
1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery.
Main Outcome Measure:
25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison).
25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (β = −0.81 [95% confidence interval −1.39, −0.22]), lower compliance with study medication (%) (β = −0.28 [−0.072, −0.48]), lower early pregnancy 25(OH)D (nmol/L) (β = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (β = −10.5 [−6.4, −14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation.
Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.
Within the treatment arm of the MAVIDOS RCT, poorer 25(OH)D response to 1000IU/d cholecalciferol was associated with lower initial 25(OH)D, greater pregnancy weight gain and delivery in winter.
PMCID: PMC5155676  PMID: 27788053
10.  A comparative evaluation of the effect of polymer chemistry and fiber orientation on mesenchymal stem cell differentiation 
Bioengineered tissue scaffolds in combination with cells hold great promise for tissue regeneration. The aim of this study was to determine how the chemistry and fiber orientation of engineered scaffolds affect the differentiation of mesenchymal stem cells (MSCs). Adipogenic, chondrogenic, and osteogenic differentiation on aligned and randomly orientated electrospun scaffolds of Poly (lactic‐co‐glycolic) acid (PLGA) and Polydioxanone (PDO) were compared. MSCs were seeded onto scaffolds and cultured for 14 days under adipogenic‐, chondrogenic‐, or osteogenic‐inducing conditions. Cell viability was assessed by alamarBlue metabolic activity assays and gene expression was determined by qRT‐PCR. Cell‐scaffold interactions were visualized using fluorescence and scanning electron microscopy. Cells grew in response to scaffold fiber orientation and cell viability, cell coverage, and gene expression analysis showed that PDO supports greater multilineage differentiation of MSCs. An aligned PDO scaffold supports highest adipogenic and osteogenic differentiation whereas fiber orientation did not have a consistent effect on chondrogenesis. Electrospun scaffolds, selected on the basis of fiber chemistry and alignment parameters could provide great therapeutic potential for restoration of fat, cartilage, and bone tissue. This study supports the continued investigation of an electrospun PDO scaffold for tissue repair and regeneration and highlights the potential of optimizing fiber orientation for improved utility. © 2016 The Authors Journal of Biomedical Materials Research Part A Published by Wiley Periodicals, Inc. J Biomed Mater Res Part A: 104A: 2843–2853, 2016.
PMCID: PMC5053290  PMID: 27399850
electrospinning; PDO; PLGA; mesenchymal stem cells
11.  H3K27me3 demethylases regulate in vitro chondrogenesis and chondrocyte activity in osteoarthritis 
Epigenetic changes (i.e., chromatin modifications) occur during chondrogenesis and in osteoarthritis (OA). We investigated the effect of H3K27me3 demethylase inhibition on chondrogenesis and assessed its utility in cartilage tissue engineering and in understanding cartilage destruction in OA.
We used a high-content screen to assess the effect of epigenetic modifying compounds on collagen output during chondrogenesis of monolayer human mesenchymal stem cells (MSCs). The impact of GSK-J4 on gene expression, glycosaminoglycan output and collagen formation during differentiation of MSCs into cartilage discs was investigated. Expression of lysine (K)-specific demethylase 6A (UTX) and Jumonji domain-containing 3 (JMJD3), the HEK27Me3 demethylases targeted by GSK-J4, was measured in damaged and undamaged cartilage from patients with OA. The impact of GSK-J4 on ex vivo cartilage destruction and expression of OA-related genes in human articular chondrocytes (HACs) was assessed. H3K27Me3 demethylase regulation of transforming growth factor (TGF)-β-induced gene expression was measured in MSCs and HACs.
Treatment of chondrogenic MSCs with the H3K27me3 demethylase inhibitor GSK-J4, which targets JMJD3 and UTX, inhibited collagen output; expression of chondrogenic genes, including SOX9 and COL2A1; and disrupted glycosaminoglycan and collagen synthesis. JMJD3 but not UTX expression was increased during chondrogenesis and in damaged OA cartilage, suggesting a predominant role of JMJD3 in chondrogenesis and OA. GSK-J4 prevented ex vivo cartilage destruction and expression of the OA-related genes MMP13 and PTGS2. TGF-β is a key regulator of chondrogenesis and articular cartilage homeostasis, and TGF-β-induced gene expression was inhibited by GSK-J4 treatment of both chondrogenic MSCs and HACs.
Overall, we show that H3K27me3 demethylases modulate chondrogenesis and that enhancing this activity may improve production of tissue-engineered cartilage. In contrast, targeted inhibition of H3K27me3 demethylases could provide a novel approach in OA therapeutics.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-016-1053-7) contains supplementary material, which is available to authorized users.
PMCID: PMC4936015  PMID: 27388528
Epigenetics; TGF-β; Osteoarthritis; JMJD3; Histone demethylase
12.  Replication of Associations of Genetic Loci Outside the HLA Region With Susceptibility to Anti–Cyclic Citrullinated Peptide–Negative Rheumatoid Arthritis 
Genetic polymorphisms within the HLA region explain only a modest proportion of anti–cyclic citrullinated peptide (anti‐CCP)–negative rheumatoid arthritis (RA) heritability. However, few non‐HLA markers have been identified so far. This study was undertaken to replicate the associations of anti‐CCP–negative RA with non‐HLA genetic polymorphisms demonstrated in a previous study.
The Rheumatoid Arthritis Consortium International densely genotyped 186 autoimmune‐related regions in 3,339 anti‐CCP–negative RA patients and 15,870 controls across 6 different populations using the Illumina ImmunoChip array. We performed a case–control replication study of the anti‐CCP–negative markers with the strongest associations in that discovery study, in an independent cohort of anti‐CCP–negative UK RA patients. Individuals from the arcOGEN Consortium and Wellcome Trust Case Control Consortium were used as controls. Genotyping in cases was performed using Sequenom MassArray technology. Genome‐wide data from controls were imputed using the 1000 Genomes Phase I integrated variant call set release version 3 as a reference panel.
After genotyping and imputation quality control procedures, data were available for 15 non‐HLA single‐nucleotide polymorphisms in 1,024 cases and 6,348 controls. We confirmed the known markers ANKRD55 (meta‐analysis odds ratio [OR] 0.80; P = 2.8 × 10−13) and BLK (OR 1.13; P = 7.0 × 10−6) and identified new and specific markers of anti‐CCP–negative RA (prolactin [PRL] [OR 1.13; P = 2.1 × 10−6] and NFIA [OR 0.85; P = 2.5 × 10−6]). Neither of these loci is associated with other common, complex autoimmune diseases.
Anti‐CCP–negative RA and anti‐CCP–positive RA are genetically different disease subsets that only partially share susceptibility factors. Genetic polymorphisms located near the PRL and NFIA genes represent examples of genetic susceptibility factors specific for anti‐CCP–negative RA.
PMCID: PMC4924598  PMID: 26895230
13.  Inflammation activation and resolution in human tendon disease 
Science translational medicine  2015;7(311):311ra173.
Improved understanding of the role of inflammation in tendon disease is required to facilitate therapeutic target discovery. We studied supraspinatus tendons from patients experiencing pain before and after surgical subacromial decompression treatment. Tendons were classified as having early, intermediate or advanced disease and inflammation was characterized through activation of pathways mediated by Interferon, NF-κB, glucocorticoid receptor and STAT-6. Inflammation signatures revealed expression of genes and proteins induced by Interferon and NF-κB in early stage disease and genes and proteins induced by STAT-6 and glucocorticoid receptor activation in advanced stage disease. The pro-resolving proteins FPR2/ALX and ChemR23 were increased in early stage disease compared to intermediate-advanced stage disease. Patients who were pain-free post-treatment had tendons with increased expression of CD206 and ALOX15 mRNA compared to tendons from patients who continued to experience pain post-treatment, suggesting that these genes and their pathways may moderate tendon pain. Stromal cells from diseased tendons cultured in vitro showed increased expression of NF-κB and Interferon target genes after treatment with lipopolysaccharide or IFNγ compared to stromal cells derived from healthy tendons. We identified 15-epi Lipoxin A4, a stable lipoxin metabolite derived from aspirin treatment, as potentially beneficial in the resolution of tendon inflammation.
PMCID: PMC4883654  PMID: 26511510
14.  Investigation of Association Between Hip Osteoarthritis Susceptibility Loci and Radiographic Proximal Femur Shape 
To test whether previously reported hip morphology or osteoarthritis (OA) susceptibility loci are associated with proximal femur shape as represented by statistical shape model (SSM) modes and as univariate or multivariate quantitative traits.
We used pelvic radiographs and genotype data from 929 subjects with unilateral hip OA who had been recruited previously for the Arthritis Research UK Osteoarthritis Genetics Consortium genome‐wide association study. We built 3 SSMs capturing the shape variation of the OA‐unaffected proximal femur in the entire mixed‐sex cohort and for male/female‐stratified cohorts. We selected 41 candidate single‐nucleotide polymorphisms (SNPs) previously reported as being associated with hip morphology (for replication analysis) or OA (for discovery analysis) and for which genotype data were available. We performed 2 types of analysis for genotype–phenotype associations between these SNPs and the modes of the SSMs: 1) a univariate analysis using individual SSM modes and 2) a multivariate analysis using combinations of SSM modes.
The univariate analysis identified association between rs4836732 (within the ASTN2 gene) and mode 5 of the female SSM (P = 0.0016) and between rs6976 (within the GLT8D1 gene) and mode 7 of the mixed‐sex SSM (P = 0.0003). The multivariate analysis identified association between rs5009270 (near the IFRD1 gene) and a combination of modes 3, 4, and 9 of the mixed‐sex SSM (P = 0.0004). Evidence of associations remained significant following adjustment for multiple testing. All 3 SNPs had previously been associated with hip OA.
These de novo findings suggest that rs4836732, rs6976, and rs5009270 may contribute to hip OA susceptibility by altering proximal femur shape.
PMCID: PMC4864451  PMID: 25939412
15.  Once-daily maraviroc versus tenofovir/emtricitabine each combined with darunavir/ritonavir for initial HIV-1 treatment 
AIDS (London, England)  2016;30(8):1229-1238.
The aim of this study was to evaluate the efficacy of maraviroc along with darunavir/ritonavir, all once daily, for the treatment of antiretroviral-naive HIV-1 infected individuals.
MODERN was a multicentre, double-blind, noninferiority, phase III study in HIV-1 infected, antiretroviral-naive adults with plasma HIV-1 RNA at least 1000 copies/ml and no evidence of reduced susceptibility to study drugs.
At screening, participants were randomized 1 : 1 to undergo either genotypic or phenotypic tropism testing. Participants with CCR5-tropic HIV-1 were randomized 1 : 1 to receive maraviroc 150 mg once daily or tenofovir/emtricitabine once daily each with darunavir/ritonavir once daily for 96 weeks. The primary endpoint was the proportion of participants with HIV-1 RNA less than 50 copies/ml (Food and Drug Administration snapshot algorithm) at Week 48. A substudy evaluated bone mineral density, body fat distribution and serum bone turnover markers.
Seven hundred and ninety-seven participants were dosed (maraviroc, n = 396; tenofovir/emtricitabine, n = 401). The Data Monitoring Committee recommended early study termination due to inferior efficacy in the maraviroc group. At Week 48, the proportion of participants with HIV-1 RNA less than 50 copies/ml was 77.3% for maraviroc and 86.8% for tenofovir/emtricitabine [difference of −9.54% (95% confidence interval: −14.83 to −4.24)]. More maraviroc participants discontinued for lack of efficacy, which was not associated with non-R5 tropism or resistance. Discontinuations for adverse events, Category C events, Grade 3/4 adverse events and laboratory abnormalities were similar between groups.
A once-daily nucleos(t)ide-sparing two-drug regimen of maraviroc and darunavir/ritonavir was inferior to a three-drug regimen of tenofovir/emtricitabine and darunavir/ritonavir in antiretroviral-naive adults.
PMCID: PMC4856180  PMID: 26854810
darunavir; emtricitabine; HIV-1; maraviroc; nucleos(t)ide-sparing regimen; tenofovir; treatment-naive
16.  A survey on beliefs and attitudes of trainee surgeons towards placebo 
BMC Surgery  2016;16:27.
The aim of this study was to investigate the beliefs and attitudes of trainee surgeons regarding placebo interventions, in surgical practice and in research, and to compare them to those of senior orthopaedic surgeons.
An invitation to participate in an online survey was sent to all the email addresses in the members’ database of the British Orthopaedic Trainees Association (BOTA).
All 987 members of BOTA were invited to participate in the survey and 189 responded (19 %). The majority of trainees think that the placebo effect is real (88 %), has therapeutic benefits (88 %) and that placebo manipulations are permissible (98 %). Sixty per cent of respondents agree that placebo can be used outside of research, most commonly, to distinguish between organic and non-organic symptoms (36 %). Trainees are more likely than senior surgeons to use placebo for pain management (34 % vs. 12 %). They are mainly concerned about the risk of side effects associated with the use of placebo (80 %) and prefer placebo interventions with minimal invasiveness. Seventy-three per cent respondents would recruit patients into the proposed randomised controlled surgical trial.
The views regarding efficacy, permissibility and indications for placebo among trainees are similar to those of orthopaedic consultants. Orthopaedic trainees regard placebo as permissible and show willingness to recruit into placebo-controlled trials. However, they seem to have limited understanding of mechanisms of placebo effect and underestimate its ubiquity.
Electronic supplementary material
The online version of this article (doi:10.1186/s12893-016-0142-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4847348  PMID: 27118280
Orthopaedics; Placebos; Surgery; Attitudes and Beliefs
17.  Lovastatin‐Mediated Changes in Human Tendon Cells 
Journal of Cellular Physiology  2015;230(10):2543-2551.
Statins are among the most widely prescribed drugs worldwide. Numerous studies have shown their beneficial effects in prevention of cardiovascular disease through cholesterol‐lowering and anti‐atherosclerotic properties. Although some statin patients may experience muscle‐related symptoms, severe side effects of statin therapy are rare, primarily due to extensive first‐pass metabolism in the liver. Skeletal muscles appear to be the main site of side effects; however, recently some statin‐related adverse effects have been described in tendon. The mechanism behind these side effects remains unknown. This is the first study that explores tendon‐specific effects of statins in human primary tenocytes. The cells were cultured with different concentrations of lovastatin for up to 1 week. No changes in cell viability or morphology were observed in tenocytes incubated with therapeutic doses. Short‐term exposure to lovastatin concentrations outside the therapeutic range had no effect on tenocyte viability; however, cell migration was reduced. Simvastatin and atorvastatin, two other drug family members, also reduced the migratory properties of the cells. Prolonged exposure to high concentrations of lovastatin induced changes in cytoskeleton leading to cell rounding and decreased levels of mRNA for matrix proteins, but increased BMP‐2 expression. Gap junctional communication was impaired but due to cell shape change and separation rather than direct gap junction inhibition. These effects were accompanied by inhibition of prenylation of Rap1a small GTPase. Collectively, we showed that statins in a dose‐dependent manner decrease migration of human tendon cells, alter their expression profile and impair the functional network, but do not inhibit gap junction function. J. Cell. Physiol. 230: 2543–2551, 2015. © 2015 The Authors. Journal of Cellular Physiology Published by Wiley Periodicals, Inc.
PMCID: PMC4832302  PMID: 25846724
18.  Prevalence and risk factors for low bone mineral density in untreated HIV infection: a substudy of the INSIGHT Strategic Timing of AntiRetroviral Treatment trial 
HIV medicine  2015;16(0 1):137-146.
HIV infection is associated with a higher prevalence of low bone mineral density (BMD) and fractures than the general population. There are limited data in HIV-positive adults, naïve to antiretroviral therapy (ART), to estimate the relative contribution of untreated HIV to bone loss.
The START Bone Mineral Density substudy is a randomised comparison of the effect of immediate versus deferred initial ART on bone. We evaluated traditional, demographic, HIV-related, and immunological factors for their associations with baseline hip and lumbar spine BMD, measured by dual-energy x-ray absorptiometry, using multiple regression.
A total of 424 ART-naïve participants were enrolled at 33 sites in six continents; mean (SD) age was 34 (10.1) years, 79.0% were nonwhite, 26.0% were women, and 12.5% had a body mass index (BMI) <20 kg/m2. Mean (SD) Z-scores were -0.41 (0.94) at the spine and -0.36 (0.88) for total hip; 1.9% had osteoporosis and 35.1% had low BMD (hip or spine T-score <-1.0). Factors independently associated with lower BMD at the hip and spine were female sex, Latino/Hispanic ethnicity, lower BMI and higher estimated glomerular filtration rate. Longer time since HIV diagnosis was associated with lower hip BMD. Current or nadir CD4 cell counts, and HIV viral load were not associated with BMD.
In this geographically and racially diverse population of ART-naïve adults with normal CD4 cell counts, low BMD was common, but osteoporosis was rare. Lower BMD was significantly associated with traditional risk factors but not with CD4 cell count or viral load.
PMCID: PMC4341957  PMID: 25711332
HIV; antiretroviral therapy; ART-naïve; bone mineral density
19.  Feasibility of surgical randomised controlled trials with a placebo arm: a systematic review 
BMJ Open  2016;6(3):e010194.
To find evidence, either corroborating or refuting, for many persisting beliefs regarding the feasibility of carrying out surgical randomised controlled trials with a placebo arm, with emphasis on the challenges related to recruitment, funding, anaesthesia or blinding.
Systematic review.
Data sources and study selection
The analysis involved studies published between 1959 and 2014 that were identified during an earlier systematic review of benefits and harms of placebo-controlled surgical trials published in 2014.
63 trials were included in the review. The main problem reported in many trials was a very slow recruitment rate, mainly due to the difficulty in finding eligible patients. Existing placebo trials were funded equally often from commercial and non-commercial sources. General anaesthesia or sedation was used in 41% of studies. Among the reviewed trials, 81% were double-blinded, and 19% were single-blinded. Across the reviewed trials, 96% (range 50–100%) of randomised patients completed the study. The withdrawal rate during the study was similar in the surgical and in the placebo groups.
This review demonstrated that placebo-controlled surgical trials are feasible, at least for procedures with a lower level of invasiveness, but also that recruitment is difficult. Many of the presumed challenges to undertaking such trials, for example, funding, anaesthesia or blinding of patients and assessors, were not reported as obstacles to completion in any of the reviewed trials.
PMCID: PMC4800115  PMID: 27008687
SURGERY; Randomised Controlled Trials; Placebos
20.  Enabling Consistency in Pluripotent Stem Cell-Derived Products for Research and Development and Clinical Applications Through Material Standards 
This article discusses the need for reference materials, potential challenges faced by human pluripotent stem cell-derived products, and possible approaches to alleviating concerns about consistency and reproducibility in their production. It is hoped that the research community and tool providers will engage to assess and incorporate into practice potential approaches, as appropriate, and that novel thinking will lead to approaches that more satisfactorily fulfill the needs outlined.
There is a need for physical standards (reference materials) to ensure both reproducibility and consistency in the production of somatic cell types from human pluripotent stem cell (hPSC) sources. We have outlined the need for reference materials (RMs) in relation to the unique properties and concerns surrounding hPSC-derived products and suggest in-house approaches to RM generation relevant to basic research, drug screening, and therapeutic applications. hPSCs have an unparalleled potential as a source of somatic cells for drug screening, disease modeling, and therapeutic application. Undefined variation and product variability after differentiation to the lineage or cell type of interest impede efficient translation and can obscure the evaluation of clinical safety and efficacy. Moreover, in the absence of a consistent population, data generated from in vitro studies could be unreliable and irreproducible. Efforts to devise approaches and tools that facilitate improved consistency of hPSC-derived products, both as development tools and therapeutic products, will aid translation. Standards exist in both written and physical form; however, because many unknown factors persist in the field, premature written standards could inhibit rather than promote innovation and translation. We focused on the derivation of physical standard RMs. We outline the need for RMs and assess the approaches to in-house RM generation for hPSC-derived products, a critical tool for the analysis and control of product variation that can be applied by researchers and developers. We then explore potential routes for the generation of RMs, including both cellular and noncellular materials and novel methods that might provide valuable tools to measure and account for variation. Multiparametric techniques to identify “signatures” for therapeutically relevant cell types, such as neurons and cardiomyocytes that can be derived from hPSCs, would be of significant utility, although physical RMs will be required for clinical purposes.
PMCID: PMC4339854  PMID: 25650438
21.  Comparison of transforming growth factor beta expression in healthy and diseased human tendon 
Diseased tendons are characterised by fibrotic scar tissue, which adversely affects tendon structure and function and increases the likelihood of re-injury. The mechanisms and expression profiles of fibrosis in diseased tendon is understudied compared to pulmonary and renal tissues, where transforming growth factor (TGF)β and its associated superfamily are known to be key drivers of fibrosis and modulate extracellular matrix homeostasis. We hypothesised that differential expression of TGFβ superfamily members would exist between samples of human rotator cuff tendons with established disease compared to healthy control tendons.
Healthy and diseased rotator cuff tendons were collected from patients presenting to an orthopaedic referral centre. Diseased tendinopathic (intact) and healthy rotator cuff tendons were collected via ultrasound-guided biopsy and torn tendons were collected during routine surgical debridement. Immunohistochemistry and quantitative real-time polymerase chain reaction were used to investigate the protein and gene expression profiles of TGFβ superfamily members in these healthy and diseased tendons.
TGFβ superfamily members were dysregulated in diseased compared to healthy tendons. Specifically, TGFβ-1, TGFβ receptor (R)1 and TGFβ R2 proteins were reduced (p < 0.01) in diseased compared to healthy tendons. At the mRNA level, TGFβ R1 was significantly reduced in samples of diseased tendons, whereas TGFβ R2 was increased (p < 0.01). BMP-2, BMP-7 and CTGF mRNA remained unchanged with tendon disease.
We propose that downregulation of TGFβ pathways in established tendon disease may be a protective response to limit disease-associated fibrosis. The disruption of the TGFβ axis with disease suggests associated downstream pathways may be important for maintaining healthy tendon homeostasis. The findings from our study suggest that patients with established tendon disease would be unlikely to benefit from therapeutic TGFβ blockade, which has been investigated as a treatment strategy in several animal models. Future studies should investigate the expression profile of fibrotic mediators in earlier stages of tendon disease to improve understanding of the targetable mechanisms underpinning tendon fibrosis.
PMCID: PMC4756520  PMID: 26883016
Tendon; Tendinopathy; Fibrosis; TGFβ
22.  Loss to follow-up in the Australian HIV Observational Database 
Antiviral therapy  2014;20(7):731-741.
Loss to follow-up (LTFU) in HIV-positive cohorts is an important surrogate for interrupted clinical care which can potentially influence the assessment of HIV disease status and outcomes. After preliminary evaluation of LTFU rates and patient characteristics, we evaluated the risk of mortality by LTFU status in a high resource setting.
Rates of LTFU were measured in the Australian HIV Observational Database for a range of patient characteristics. Multivariate repeated measures regression methods were used to identify determinants of LTFU. Mortality by LTFU status was ascertained using linkage to the National Death Index. Survival following combination antiretroviral therapy initiation was investigated using the Kaplan-Meier (KM) method and Cox proportional hazards models.
Of 3,413 patients included in this analysis, 1,632 (47.8%) had at least one episode of LTFU after enrolment. Multivariate predictors of LTFU included viral load (VL)>10,000 copies/ml (Rate ratio (RR) 1.63 (95% confidence interval (CI):1.45–1.84) (ref ≤400)), time under follow-up (per year) (RR 1.03 (95% CI: 1.02–1.04)) and prior LTFU (per episode) (RR 1.15 (95% CI: 1.06–1.24)). KM curves for survival were similar by LTFU status (p=0.484). LTFU was not associated with mortality in Cox proportional hazards models (univariate hazard ratio (HR) 0.93 (95% CI: 0.69–1.26) and multivariate HR 1.04 (95% CI: 0.77–1.43)).
Increased risk of LTFU was identified amongst patients with potentially higher infectiousness. We did not find significant mortality risk associated with LTFU. This is consistent with timely re-engagement with treatment, possibly via high levels of unreported linkage to other health care providers.
PMCID: PMC4424189  PMID: 25377928
23.  Assessment of Osteoarthritis Candidate Genes in a Meta-Analysis of Nine Genome-Wide Association Studies 
To assess candidate genes for association with osteoarthritis (OA) and identify promising genetic factors and, secondarily, to assess the candidate gene approach in OA.
A total of 199 candidate genes for association with OA were identified using Human Genome Epidemiology (HuGE) Navigator. All of their single-nucleotide polymorphisms (SNPs) with an allele frequency of >5% were assessed by fixed-effects meta-analysis of 9 genome-wide association studies (GWAS) that included 5,636 patients with knee OA and 16,972 control subjects and 4,349 patients with hip OA and 17,836 control subjects of European ancestry. An additional 5,921 individuals were genotyped for significantly associated SNPs in the meta-analysis. After correction for the number of independent tests, P values less than 1.58 × 10−5 were considered significant.
SNPs at only 2 of the 199 candidate genes (COL11A1 and VEGF) were associated with OA in the meta-analysis. Two SNPs in COL11A1 showed association with hip OA in the combined analysis: rs4907986 (P = 1.29 × 10−5, odds ratio [OR] 1.12, 95% confidence interval [95% CI] 1.06−1.17) and rs1241164 (P = 1.47 × 10−5, OR 0.82, 95% CI 0.74−0.89). The sex-stratified analysis also showed association of COL11A1 SNP rs4908291 in women (P = 1.29 × 10−5, OR 0.87, 95% CI 0.82−0.92); this SNP showed linkage disequilibrium with rs4907986. A single SNP of VEGF, rs833058, showed association with hip OA in men (P = 1.35 × 10−5, OR 0.85, 95% CI 0.79−0.91). After additional samples were genotyped, association at one of the COL11A1 signals was reinforced, whereas association at VEGF was slightly weakened.
Two candidate genes, COL11A1 and VEGF, were significantly associated with OA in this focused meta-analysis. The remaining candidate genes were not associated.
PMCID: PMC4660891  PMID: 24757145

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