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1.  Differences in glutamate receptors and inflammatory cell numbers are associated with the resolution of pain in human rotator cuff tendinopathy 
The relationship between peripheral tissue characteristics and pain symptoms in soft tissue inflammation is poorly understood. The primary aim of this study was to determine immunohistochemical differences in tissue obtained from patients with persistent pain and patients who had become pain-free after surgical treatment for rotator cuff tendinopathy. The secondary aim was to investigate whether there would be differences in glutaminergic and inflammatory gene expression between disease-derived and healthy control cells in vitro.
Supraspinatus tendon biopsies were obtained from nine patients with tendon pain before shoulder surgery and from nine further patients whose pain had resolved completely following shoulder surgery. Histological markers relating to the basic tendon characteristics, inflammation and glutaminergic signalling were quantified by immunohistochemical analysis. Gene expression of glutaminergic and inflammatory markers was determined in tenocyte explants derived from painful rotator cuff tendon tears in a separate cohort of patients and compared to that of explants from healthy control tendons. Dual labelling was performed to identify cell types expressing nociceptive neuromodulators.
Tendon samples from patients with persistent pain demonstrated increased levels of metabotropic glutamate receptor 2 (mGluR2), kainate receptor 1 (KA1), protein gene product 9.5 (PGP9.5), CD206 (macrophage marker) and CD45 (pan-leucocyte marker) versus pain-free controls (p <0.05). NMDAR1 co-localised with CD206-positive cells, whereas PGP9.5 and glutamate were predominantly expressed by resident tendon cells. These results were validated by in vitro increases in the expression of mGluR2, N-methyl-D-aspartate receptor (NMDAR1), KA1, CD45, CD206 and tumour necrosis factor alpha (TNF-α) genes (p <0.05) in disease-derived versus control cells.
We conclude that differences in glutamate receptors and inflammatory cell numbers are associated with the resolution of shoulder pain in rotator cuff tendinopathy, and that disease-derived cells exhibit a distinctly different neuro-inflammatory gene expression profile to healthy control cells.
Electronic supplementary material
The online version of this article (doi:10.1186/s13075-015-0691-5) contains supplementary material, which is available to authorized users.
PMCID: PMC4498529  PMID: 26160609
2.  Cell proliferation is a key determinant of the outcome of FOXO3a activation 
The FOXO family of forkhead transcription factors have a pivotal role in determining cell fate in response to oxidative stress. FOXO activity can either promote cell survival or induce cell death. Increased FOXO-mediated cell death has been implicated in the pathogenesis of degenerative diseases affecting musculoskeletal tissues. The aim of this study was to determine the conditions under which one member of the FOXO family, FOXO3a, promotes cell survival as opposed to cell death. Treatment of primary human tenocytes with 1 pM hydrogen peroxide for 18 h resulted in increased protein levels of FOXO3a. In peroxide-treated cells cultured in low serum media, FOXO3a inhibited cell proliferation and protected against apoptosis. However in peroxide treated cells cultured in high serum media, cell proliferation was unchanged but level of apoptosis significantly increased. Similarly, in tenocytes transduced to over-express FOXO3a, cell proliferation was inhibited and level of apoptosis unchanged in cells cultured in low serum. However there was a robust increase in cell death in FOXO3a-expressing cells cultured in high serum. Inhibition of cell proliferation in either peroxide-treated or FOXO3a-expressing cells cultured in high serum protected against apoptosis induction. Conversely, addition of a Chk2 inhibitor to peroxide-treated or FOXO3a-expressing cells overrode the inhibitory effect of FOXO3a on cell proliferation and led to increased apoptosis in cells cultured in low serum. This study demonstrates that proliferating cells may be particularly susceptible to the apoptosis-inducing actions of FOXO3a. Inhibition of cell proliferation by FOXO3a may be a critical event in allowing the pro-survival rather than the pro-apoptotic activity of FOXO3a to prevail.
•FOXO3a activity can result in either promotion of cell survival or apoptosis.•The outcome of FOXO3a activation differs in proliferating compared to non-proliferating cells.•Proliferating cells are susceptible to FOXO3a-mediated apoptosis.•Inhibition of cell proliferation by FOXO3a promotes cell survival.
PMCID: PMC4449364  PMID: 25935481
Forkhead transcription factors; Cell death; Cell survival; Oxidative stress; Apoptosis
3.  HIV-associated neurocognitive disorder in Australia: a case of a high-functioning and optimally treated cohort and implications for international neuro HIV research 
Journal of neurovirology  2014;20(3):258-268.
The Australian HIV-infected (HIV+) population is largely comprised of high-functioning men who have sex with men (MSM). Like other English-speaking countries, Australia mostly relies on US neuropsychological normative standards to detect and determine the prevalence of neurological disorders. Whether the US neuropsychological (NP) normative standards are appropriate in Australian HIV+ MSM has not been established. Ninety virally suppressed HIV+ and 49 HIV-uninfected (HIV−) men (respectively 86 and 85 % self-reported MSM; mean age 54 and 56 years, mean premorbid verbal IQ estimate 110 and 111) undertook standard NP testing. The raw neuropsychological data were transformed using the following: (1) US standards as uncorrected scaled scores and demographically corrected T scores (US norms); and (2) z scores (without demographic corrections) derived from Australian comparison group scaled scores (local norms). To determine HIV-associated neurocognitive disorder prevalence, we used a standard definition of impairment based upon a battery-wide summary score: the global deficit score (GDS). Impairment classification (GDS≥0.5) based on the local norms was best at discriminating between the two groups (HIV−=14.3 % vs. HIV+ = 53.3 %; p<0.0001). This definition was significantly associated with age. Impairment classification based on the US norms yielded much lower impairment rate regardless of the HIV status (HIV−=4.1 % vs. HIV+=14.7 %; p= 0.05), but was associated with historical AIDS, and not age. Both types of summary scores were associated with reduced independence in activities of daily living (p≤ 0.03). Accurate neuropsychological classifications of high (or low) functioning individuals may need country-specific norms that correct for performance-based (e.g., reading) estimates of premorbid cognition in addition to the traditional demographic factors.
PMCID: PMC4268870  PMID: 24696363
HIV-associated neurocognitive disorder; Neuropsychological functions; Normative data; HIV/AIDS
4.  The CSAW Study (Can Shoulder Arthroscopy Work?) – a placebo-controlled surgical intervention trial assessing the clinical and cost effectiveness of arthroscopic subacromial decompression for shoulder pain: study protocol for a randomised controlled trial 
Trials  2015;16:210.
Arthroscopic subacromial decompression (ASAD) is a commonly performed surgical intervention for shoulder pain. The rationale is that removal of a bony acromial spur relieves symptoms by decompressing rotator cuff tendons passing through the subacromial space. However, the efficacy of this procedure is uncertain. The objective of this trial was to compare the efficacy and cost-effectiveness of ASAD in patients with subacromial pain using appropriate control groups, including placebo intervention.
The trial is a three-group, parallel design, pragmatic, randomised controlled study. The intervention content for each group (ASAD, active monitoring with specialist reassessment (AMSR) and investigational shoulder arthroscopy only (AO)) enables assessment of (1) the efficacy of the surgery against no surgery; (2) the need for a specific component of the surgery—namely, removal of the bony spur; and (3) quantification of the placebo effect. Concealed allocation was performed using a 1:1:1 randomisation ratio and using age, sex, baseline Oxford Shoulder Score (OSS) and centre as minimisation criteria. The primary outcome measure is the OSS at 6 months post randomisation. A total of 300 patients recruited over 24 months from a minimum of 14 UK shoulder units over 24 months were required to detect a difference of 4.5 points on the OSS (standard deviation, 9) with 90% power and to allow for 15% loss to follow-up. Secondary outcomes include cost-effectiveness, pain, complications and patient satisfaction. A substantial qualitative research component is included. The primary analysis will be conducted on the modified intention-to-treat analysis. Sensitivity analysis will be used to assess the robustness of the results with regard to the underlying assumptions about missing data using multiple imputation.
This trial uses an innovative design to account for the known placebo effects of surgery, but it also will delineate the mechanism for any benefit from surgery. The investigational AO group is considered a placebo intervention (not sham surgery), as it includes all components of subacromial decompression except the critical surgical element. Some discussion is also dedicated to the challenges of conducting placebo surgery trials.
Trial registrations
UK Clinical Research Network UKCRN12104. Registered 22 May 2012.
International Standard Randomised Controlled Trial ISRCTN33864128. Registered 22 June 2012. NCT01623011. Registered 15 June 2012.
Electronic supplementary material
The online version of this article (doi:10.1186/s13063-015-0725-y) contains supplementary material, which is available to authorized users.
PMCID: PMC4443660  PMID: 25956385
Acromion; Arthroscopy; Placebo; Randomise; Sham; Shoulder; Trial; Waiting list
5.  Large-Scale Analysis of Association Between GDF5 and FRZB Variants and Osteoarthritis of the Hip, Knee, and Hand 
Arthritis and rheumatism  2009;60(6):1710-1721.
GDF5 and FRZB have been proposed as genetic loci conferring susceptibility to osteoarthritis (OA); however, the results of several studies investigating the association of OA with the rs143383 polymorphism of the GDF5 gene or the rs7775 and rs288326 polymorphisms of the FRZB gene have been conflicting or inconclusive. To examine these associations, we performed a large-scale meta-analysis of individual-level data.
Fourteen teams contributed data on polymorphisms and knee, hip, and hand OA. For rs143383, the total number of cases and controls, respectively, was 5,789 and 7,850 for hip OA, 5,085 and 8,135 for knee OA, and 4,040 and 4,792 for hand OA. For rs7775, the respective sample sizes were 4,352 and 10,843 for hip OA, 3,545 and 6,085 for knee OA, and 4,010 and 5,151 for hand OA, and for rs288326, they were 4,346 and 8,034 for hip OA, 3,595 and 6,106 for knee OA, and 3,982 and 5,152 for hand OA. For each individual study, sex-specific odds ratios (ORs) were calculated for each OA phenotype that had been investigated. The ORs for each phenotype were synthesized using both fixed-effects and random-effects models for allele-based effects, and also for haplotype effects for FRZB.
A significant random-effects summary OR for knee OA was demonstrated for rs143383 (1.15 [95% confidence interval 1.09–1.22]) (P = 9.4 × 10−7), with no significant between-study heterogeneity. Estimates of effect sizes for hip and hand OA were similar, but a large between-study heterogeneity was observed, and statistical significance was borderline (for OA of the hip [P = 0.016]) or absent (for OA of the hand [P = 0.19]). Analyses for FRZB polymorphisms and haplotypes did not reveal any statistically significant signals, except for a borderline association of rs288326 with hip OA (P = 0.019).
Evidence of an association between the GDF5 rs143383 polymorphism and OA is substantially strong, but the genetic effects are consistent across different populations only for knee OA. Findings of this collaborative analysis do not support the notion that FRZB rs7775 or rs288326 has any sizable genetic effect on OA phenotypes.
PMCID: PMC4412885  PMID: 19479880
6.  An update to the HIV-TRePS system: the development of new computational models that do not require a genotype to predict HIV treatment outcomes 
The optimal individualized selection of antiretroviral drugs in resource-limited settings is challenging because of the limited availability of drugs and genotyping. Here we describe the development of the latest computational models to predict the response to combination antiretroviral therapy without a genotype, for potential use in such settings.
Random forest models were trained to predict the probability of a virological response to therapy (<50 copies HIV RNA/mL) following virological failure using the following data from 22 567 treatment-change episodes including 1090 from southern Africa: baseline viral load and CD4 cell count, treatment history, drugs in the new regimen, time to follow-up and follow-up viral load. The models were assessed during cross-validation and with an independent global test set of 1000 cases including 100 from southern Africa. The models' accuracy [area under the receiver-operating characteristic curve (AUC)] was evaluated and compared with genotyping using rules-based interpretation systems for those cases with genotypes available.
The models achieved AUCs of 0.79–0.84 (mean 0.82) during cross-validation, 0.80 with the global test set and 0.78 with the southern African subset. The AUCs were significantly lower (0.56–0.57) for genotyping.
The models predicted virological response to HIV therapy without a genotype as accurately as previous models that included a genotype. They were accurate for cases from southern Africa and significantly more accurate than genotyping. These models will be accessible via the online treatment support tool HIV-TRePS and have the potential to help optimize antiretroviral therapy in resource-limited settings where genotyping is not generally available.
PMCID: PMC3956369  PMID: 24275116
antiretroviral therapy; resource-limited settings; genotyping
7.  Meaningful changes for the Oxford hip and knee scores after joint replacement surgery 
To present estimates of clinically meaningful or minimal important changes for the Oxford Hip Score (OHS) and the Oxford Knee Score (OKS) after joint replacement surgery.
Study Design and Setting
Secondary data analysis of the NHS patient-reported outcome measures data set that included 82,415 patients listed for hip replacement surgery and 94,015 patients listed for knee replacement surgery was performed.
Anchor-based methods revealed that meaningful change indices at the group level [minimal important change (MIC)], for example in cohort studies, were ∼11 points for the OHS and ∼9 points for the OKS. For assessment of individual patients, receiver operating characteristic analysis produced MICs of 8 and 7 points for OHS and OKS, respectively. Additionally, the between group minimal important difference (MID), which allows the estimation of a clinically relevant difference in change scores from baseline when comparing two groups, that is, for clinical trials, was estimated to be ∼5 points for both the OKS and the OHS. The distribution-based minimal detectable change (MDC90) estimates for the OKS and OHS were 4 and 5 points, respectively.
This study has produced and discussed estimates of minimal important change/difference for the OKS/OHS. These estimates should be used in the power calculations and the interpretation of studies using the OKS and OHS. The MDC90 (∼4 points OKS and ∼5 points OHS) represents the smallest possible detectable change for each of these instruments, thus indicating that any lower value would fall within measurement error.
PMCID: PMC4270450  PMID: 25441700
Minimal important change; Minimal important difference; Hip replacement; Knee replacement; Responder definition; Study designs
8.  The Implementation of Novel Collaborative Structures for the Identification and Resolution of Barriers to Pluripotent Stem Cell Translation 
Stem Cells and Development  2013;22(Suppl 1):63-72.
Increased global connectivity has catalyzed technological development in almost all industries, in part through the facilitation of novel collaborative structures. Notably, open innovation and crowd-sourcing—of expertise and/or funding—has tremendous potential to increase the efficiency with which biomedical ecosystems interact to deliver safe, efficacious and affordable therapies to patients. Consequently, such practices offer tremendous potential in advancing development of cellular therapies.
In this vein, the CASMI Translational Stem Cell Consortium (CTSCC) was formed to unite global thought-leaders, producing academically rigorous and commercially practicable solutions to a range of challenges in pluripotent stem cell translation. Critically, the CTSCC research agenda is defined through continuous consultation with its international funding and research partners.
Herein, initial findings for all research focus areas are presented to inform global product development strategies, and to stimulate continued industry interaction around biomanufacturing, strategic partnerships, standards, regulation and intellectual property and clinical adoption.
PMCID: PMC3883132  PMID: 24304079
9.  Classification of rotator cuff tendinopathy using high definition ultrasound 
ultrasound is a valid cost effective tool in screening for rotator cuff pathology with high levels of accuracy in detecting full-thickness tears. To date there is no rotator cuff tendinopathy classification using ultrasound. The aims of this study are to define a valid high-definition ultrasound rotator cuff tendinopathy classification, which has discriminate validity between groups based upon anatomical principles.
464 women, aged 65–87, from an established general population cohort underwent bilateral shoulder ultrasound and musculoskeletal assessment. Sonographer accuracy was established in a separate study by comparing ultrasound findings to the gold standard intra-operative findings.
there were 510 normal tendons, 217 abnormal tendons, 77 partial tears, and 124 full-thickness tears. There was no statistical difference in age or the proportion with pain between the abnormal enthesis and partial tear groups, however both groups were statistically older (p<0.001) and had a greater proportion with pain (p<0.001 & p=0.050) than normal tendons. The full-thickness tears were statistically older than normal tendons (p<0.001), but not abnormal/partially torn tendons. The proportion with pain was significantly greater than both groups (p<0.001 & p=0.006). Symptomatic shoulders had a larger median tear size than asymptomatic shoulders (p=0.006). Using tear size as a predictor of pain likelihood, optimum sensitivity and specificity occurred when dividing tears into groups up to 2.5cm and >2.5cm, which corresponds with anatomical descriptions of the width of the supraspinatus tendon.
the classification system is as follows: Normal Tendons; Abnormal enthesis/Partial-thickness tear; Single tendon full-thickness tears (0–2.5cm); Multi-tendon full-thickness tears (>2.5cm).
PMCID: PMC4241433  PMID: 25489559
classification; rotator cuff; high-definition ultrasound
10.  Understanding regional variation in the use of surgery 
Lancet  2013;382(9898):1121-1129.
The use of common surgical procedures varies widely across geographical regions. Differences in illness burden, diagnostic practices, and patient attitudes about medical intervention explain regional variation in surgery rates to only a small degree. Instead, current evidence suggests that surgical variation primarily reflects differences in physician beliefs about the indications for surgery and the extent to which patient preferences are incorporated into treatment decisions. These two components of clinical decision making help explain the “surgical signatures” of specific procedures, as well as why some consistently vary more than others. Variation in clinical decision making is in turn influenced by broader environmental factors, including technology diffusion, specialist supply and local training paradigms, financial incentives, and regulatory factors, which vary across countries. Better scientific evidence about the comparative effectiveness of surgical and non-surgical interventions may help mitigate regional variation, but broader dissemination of shared decision making tools will be essential in reducing variation with preference-sensitive conditions.
PMCID: PMC4211114  PMID: 24075052
11.  Quantitative assessment of barriers to the clinical development and adoption of cellular therapies: A pilot study 
Journal of Tissue Engineering  2014;5:2041731414551764.
There has been a large increase in basic science activity in cell therapy and a growing portfolio of cell therapy trials. However, the number of industry products available for widespread clinical use does not match this magnitude of activity. We hypothesize that the paucity of engagement with the clinical community is a key contributor to the lack of commercially successful cell therapy products. To investigate this, we launched a pilot study to survey clinicians from five specialities and to determine what they believe to be the most significant barriers to cellular therapy clinical development and adoption. Our study shows that the main concerns among this group are cost-effectiveness, efficacy, reimbursement, and regulation. Addressing these concerns can best be achieved by ensuring that future clinical trials are conducted to adequately answer the questions of both regulators and the broader clinical community.
PMCID: PMC4221931  PMID: 25383173
Cell- and tissue-based therapy; translational medical research; regenerative medicine; tissue engineering; stem cells
12.  The Peripheral Neuronal Phenotype is Important in the Pathogenesis of Painful Human Tendinopathy: A Systematic Review 
The pathogenesis of tendinopathy is complex and incompletely understood. Although significant advances have been made in terms of understanding the pathological changes in both the extracellular matrix and the cells involved, relatively little is known about the role of neuronal regulation in tendinopathy. The frequent mismatch between tendon pathology and pain may be explained, in part, by differences in the peripheral neuronal phenotype of patients.
The primary purpose of this review was to determine whether evidence exists of changes in the peripheral neuronal phenotype in painful human tendinopathy and, if so, to identify the associated histological and molecular changes. The secondary purpose was to determine if any changes in the peripheral neuronal phenotype reported correlate with pain symptoms.
We conducted a systematic review of the scientific literature using the PRISMA and Cochrane guidelines. The Medline and Embase databases were searched using specific search criteria. Only studies analyzing the peripheral tissue of patients with the clinical diagnosis of tendinopathy were included. Inclusion was agreed on by two independent researchers on review of abstracts or full text.
Overall in the 27 included studies, there was clear evidence of changes in the peripheral neuronal phenotype in painful human tendinopathy. The excitatory glutaminergic system was significantly upregulated in seven studies, there was a significant increase in sensory neuropeptide expression in four studies, and there were significant changes in the molecular morphology of tenocytes, blood vessels, and nerves. In rotator cuff tendinopathy, substance P has been shown to correlate with pain and the neural density in the subacromial bursa has been shown to correlate with rest pain.
The peripheral neuronal phenotype is an important factor in the pathogenesis of painful human tendinopathy. Further research in this area specifically correlating tissue changes to clinical scores has great potential in further developing our understanding of the disease process.
PMCID: PMC3734433  PMID: 23609815
13.  Interruption or deferral of antiretroviral therapy reduces markers of bone turnover compared with continuous therapy: the SMART Body Composition Substudy 
Bone mineral density (BMD) declines significantly in HIV patients on antiretroviral therapy (ART). We compared the effects of intermittent versus continuous ART on markers of bone turnover in the Body Composition substudy of the Strategies for Management of AntiRetroviral Therapy (SMART) trial and determined whether early changes in markers predicted subsequent change in BMD. For 202 participants (median age 44 years, 17% female, 74% on ART) randomised to continuous or intermittent ART, plasma markers of inflammation and bone turnover were evaluated at baseline, months 4 and 12; BMD at the spine (dual X-ray absorptiometry [DXA] and computed tomography) and hip (DXA) was evaluated annually. Compared to the continuous ART group, mean bone-specific alkaline phosphatase (bALP), osteocalcin, procollagen type 1 N-terminal propeptide (P1NP), N-terminal cross-linking telopeptide of type 1 collagen (NTX), and C-terminal cross-linking telopeptide of type 1 collagen (βCTX) decreased significantly in the intermittent ART group, whereas RANKL and the RANKL:osteoprotegerin (OPG) ratio increased (all p≤0.002 at month 4 and month 12). Increases in bALP, osteocalcin, P1NP, NTX, and βCTX at month 4 predicted decrease in hip BMD at month 12, while increases in RANKL and the RANKL:OPG ratio at month 4 predicted increase in hip and spine BMD at month 12. This study has shown that compared with continuous ART, interruption of ART results in a reduction in markers of bone turnover and increase in BMD at hip and spine, and that early changes in markers of bone turnover predict BMD changes at 12 months.
PMCID: PMC3657331  PMID: 23299909
HIV; bone mineral density; antiretroviral therapy; bone turnover marker
14.  5-Cyano-1,3-phenyl­ene di­acetate 
In the title mol­ecule, C11H9NO4, the two acet­oxy groups are twisted from the plane of the benzene ring by 67.89 (4) and 53.30 (5)°. Both carbonyl groups are on the same side of the aromatic ring. In the crystal, weak C—H⋯O hydrogen bonds link mol­ecules into layers parallel to the ac plane. The crystal packing exhibits π–π inter­actions between the aromatic rings, indicated by a short inter­centroid distance of 3.767 (3) Å.
PMCID: PMC4051073  PMID: 24940282
15.  Efficacy of Initial Antiretroviral Therapy for HIV-1 Infection in Adults: A Systematic Review and Meta-Analysis of 114 Studies with up to 144 Weeks' Follow-Up 
PLoS ONE  2014;9(5):e97482.
A comprehensive assessment of initial HIV-1 treatment success may inform study design and treatment guidelines.
Group-based, systematic review and meta-analysis of initial antiretroviral therapy studies, in adults, of ≥48 weeks duration, reported through December 31, 2012. Size-weighted, intention-to-treat efficacy was calculated. Parameters of study design/eligibility, participant and treatment characteristics were abstracted. Multivariable, random effects, linear regression models with backwards, stepwise selection were then used to identify variables associated with efficacy.
Outcome Measures
Antiviral efficacy (undetectable plasma viral load) and premature cessation of therapy.
114 studies were included (216 treatment groups; 40,124 participants; mean CD4 count 248 cells/µL [SD 81]; mean HIV-1 plasma viral load log10 4.9 [SD 0.2]). Mean efficacy across all groups was 60% (SD 16) over a mean 82 weeks' follow-up (SD 38). Efficacy declined over time: 66% (SD 16) at 48 weeks, 60% (SD 16) at 96 weeks, 52% (SD 18) at 144 weeks. The most common reason for treatment cessation was participant decision (11%, SD 6.6). Efficacy was higher with ‘Preferred’ than ‘Alternative’ regimens (as defined by 2013 United States antiretroviral guidelines): 75% vs. 65%, respectively, difference 10%; 95%CI 7.6 to 15.4; p<0.001. In 98 groups (45%) reporting efficacy stratified by pre-treatment viral load (< or ≥100,000 copies/mL), efficacy was greater for the lower stratum (70% vs. 62%, respectively, difference 8.4%; 95%CI 6.0 to 10.9; p<0.001). This difference persisted within ‘Preferred’ regimens. Greatest efficacy was associated with use of tenofovir-emtricitabine (vs. other nucleoside analogue backbones) and integrase strand transfer inhibitors (vs. other third drug classes).
Initial antiretroviral treatments for HIV-1 to date appear to have suboptimal long-term efficacy, but are more effective when commenced at plasma viral loads <100,000 copies/mL. Rising viral load should be considered an indication for starting treatment. Integrase inhibitors offer a treatment advantage (vs. other third drug classes).
PMCID: PMC4022522  PMID: 24830290
16.  Hip Structural Parameters over 96 Weeks in HIV-Infected Adults Switching Treatment to Tenofovir-Emtricitabine or Abacavir-Lamivudine 
PLoS ONE  2014;9(4):e94858.
Therapy with tenofovir is associated with lower bone mineral density (BMD), higher markers of bone turnover and increased fracture risk in HIV-infected adults. Bone structural parameters generated by hip structural analysis may represent a separate measure of bone strength, but have not been assessed in HIV.
Dual-energy X-ray absorptiometry (DXA) scans from 254 HIV-infected adults randomised to simplify their existing dual nucleoside analogue reverse transcriptase inhibitor therapy to coformulated tenofovir-emtricitabine or abacavir-lamivudine were analysed using DXA-derived hip structural analysis software. Hip structural parameters included femoral strength index, section modulus, cross-sectional area, and cross-sectional moment of inertia. We used one-way ANOVA to test the relationship between nucleoside analogue type at baseline and structural parameters, multivariable analysis to assess baseline covariates associated with femoral strength index, and t-tests to compare mean change in structural parameters over 96 weeks between randomised groups.
Participants taking tenofovir at baseline had lower section modulus (−107.3 mm2, p = 0.001), lower cross-sectional area (−15.01 mm3, p = 0.001), and lower cross-sectional moment of inertia (−2,036.8 mm4, p = 0.007) than those receiving other nucleoside analogues. After adjustment for baseline risk factors, the association remained significant for section modulus (p = 0.008) and cross-sectional area (p = 0.002). Baseline covariates significantly associated with higher femoral strength index were higher spine T-score (p = 0.001), lower body fat mass (p<0.001), lower bone alkaline phosphatase (p = 0.025), and higher osteoprotegerin (p = 0.024). Hip structural parameters did not change significantly over 96 weeks and none was significantly affected by treatment simplification to tenofovir-emtricitabine or abacavir-lamivudine.
In this population, tenofovir use was associated with reduced composite indices of bone strength as measured by hip structural analysis, but none of the structural parameters improved significantly over 96 weeks with tenofovir cessation.
Trial Registration NCT00192634
PMCID: PMC3983265  PMID: 24722774
17.  Attitudes and Beliefs about Placebo Surgery among Orthopedic Shoulder Surgeons in the United Kingdom 
PLoS ONE  2014;9(3):e91699.
To survey surgeons on their beliefs and attitudes towards the use of placebo in surgery.
British orthopedic shoulder surgeons, attending a national conference in the United Kingdom, were asked to complete a self-report online questionnaire about their beliefs and attitudes towards the use of placebo related to surgical intervention. The survey included questions about ethical issues, the mechanism of placebo effects, and any concerns regarding its use.
100 surgeons who participated in the survey believed that placebo surgery is ethically acceptable (96%), especially as a part of a clinical trial (46%). Respondents thought that a placebo effect in surgery is real i.e. has a scientific basis (92%), that placebo can be therapeutically beneficial (77%), and that it involves psychological mechanisms (96%). Over half of the respondents (58%) have used a surgical procedure with a significant placebo component at least once in their professional career. Their main concern about placebo use in surgery was that it might involve an element of deception.
Conclusions and Implications
Surgeons generally agreed that a placebo component to surgical intervention might exist. They also supported placebo use in clinical trials and considered it ethical, providing it does not involve deception of patients. More studies are needed, particularly among other surgical specialties and with larger numbers of participants, to better understand the use of placebo in surgery.
PMCID: PMC3954758  PMID: 24632880
18.  Imaging and modeling collagen architecture from the nano to micro scale 
Biomedical Optics Express  2013;5(1):233-243.
The collagen meshwork plays a central role in the functioning of a range of tissues including cartilage, tendon, arteries, skin, bone and ligament. Because of its importance in function, it is of considerable interest for studying development, disease and regeneration processes. Here, we have used second harmonic generation (SHG) to image human tissues on the hundreds of micron scale, and developed a numerical model to quantitatively interpret the images in terms of the underlying collagen structure on the tens to hundreds of nanometer scale. Focusing on osteoarthritic changes in cartilage, we have demonstrated that this combination of polarized SHG imaging and numerical modeling can estimate fibril diameter, filling fraction, orientation and bundling. This extends SHG microscopy from a qualitative to quantitative imaging technique, providing a label-free and non-destructive platform for characterizing the extracellular matrix that can expand our understanding of the structural mechanisms in disease.
PMCID: PMC3891335  PMID: 24466490
(170.0170) Medical optics and biotechnology; (190.0190) Nonlinear optics
19.  Corticosteroid injection for shoulder pain: single-blind randomized pilot trial in primary care 
Trials  2013;14:425.
Shoulder pain is a very common presentation in primary care. Evidence of benefit for subacromial corticosteroid injection is inconclusive and confined largely to studies with short follow-up. We plan a large, definitive, primary-care-based trial to determine efficacy and safety in patients with rotator cuff tendinopathy, and conducted a pilot trial to explore feasibility.
Six general practitioners (GPs) from Oxfordshire, UK underwent update training in assessing painful shoulders and injecting the subacromial space. Each then recruited patients aged 35 to 74 years from primary care complaining of shoulder pain lasting no more than 6 months. Eligible participants were randomized to receive either methylprednisolone acetate 40 mg with lidocaine 1% (total volume 1 ml), or lidocaine 1% alone (total volume 1 ml), injected into the subacromial space. The participants were blinded to treatment allocation. Feasibility outcomes were rates of recruitment, withdrawal, adherence to the protocol, completeness of follow-up, and success of patient masking. Clinical outcomes were the Oxford Shoulder Score (OSS) at baseline and at 4 and 12 weeks, and responses to three satisfaction questions at 2, 4 and 12 weeks. Outcome data were collected by postal questionnaires.
A total of 40 participants were randomized (80% of the target 50 participants) over 26 weeks giving an overall recruitment rate of 1.5 participants per week. Rates of follow-up were maintained to a high level for the full 12 weeks. Four participants requested a ‘rescue’ corticosteroid injection but no patients withdrew. The trial GPs gave high scores for their confidence that the patient had remained blinded to treatment allocation during the procedure. The OSS at 4 and 12 weeks and the responses to the satisfaction questions are reported.
It is feasible to recruit participants with shoulder pain in the primary care setting for a blinded, randomized trial of corticosteroid injection. Online randomization of participants from the practice is also feasible, and postal questionnaires provide an effective means of gathering outcome data in this area of study. The lessons learned from this pilot will usefully inform the design of a large, definitive efficacy trial in primary care.
Trial registration
Current Clinical Trials ISRCTN82357435
PMCID: PMC3878869  PMID: 24325987
Shoulder pain; Rotator cuff; Tendinopathy; Injection
22.  Challenges in the design and analysis of surgical trials 
Trials  2013;14(Suppl 1):P31.
PMCID: PMC3980823
24.  What influences surgeons’ experience of surgical research? 
Trials  2013;14(Suppl 1):P80.
PMCID: PMC3981155

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