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.
Minimal important change; Minimal important difference; Hip replacement; Knee replacement; Responder definition; Study designs
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.
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).
classification; rotator cuff; high-definition ultrasound
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.
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.
Cell- and tissue-based therapy; translational medical research; regenerative medicine; tissue engineering; stem cells
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.
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.
HIV; bone mineral density; antiretroviral therapy; bone turnover marker
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.
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.
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).
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.
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.
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.
(170.0170) Medical optics and biotechnology; (190.0190) Nonlinear optics
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.
Current Clinical Trials ISRCTN82357435
Shoulder pain; Rotator cuff; Tendinopathy; Injection
In the majority of patients with osteoarthritis of the knee the disease originates in the medial compartment. There are two fundamentally different approaches to knee replacement for patients with unicompartmental disease: some surgeons feel that it is always best to replace both the knee compartments with a total knee replacement (TKR); whereas others feel it is best to replace just the damaged component of the knee using a partial or unicompartment replacement (UKR). Both interventions are established and well-documented procedures. Little evidence exists to prove the clinical and cost-effectiveness of either management option. This provides an explanation for the high variation in treatment of choice by individual surgeons for the same knee pathology.
The aim of the TOPKAT study will be to assess the clinical and cost effectiveness of TKRs compared to UKRs in patients with medial compartment osteoarthritis.
The design of the study is a single layer multicentre superiority type randomised controlled trial of unilateral knee replacement patients. Blinding will not be possible as the surgical scars for each procedure differ.
We aim to recruit 500 patients from approximately 28 secondary care orthopaedic units from across the UK including district general and teaching hospitals. Participants will be randomised to either UKR or TKR. Randomisation will occur using a web-based randomisation system. The study is pragmatic in terms of implant selection for the knee replacement operation. Participants will be followed up for 5 years. The primary outcome is the Oxford Knee Score, which will be collected via questionnaires at 2 months, 1 year and then annually to 5 years. Secondary outcomes will include cost-effectiveness, patient satisfaction and complications data.
Current Controlled Trials ISRCTN03013488; ClinicalTrials.gov Identifier: NCT01352247
Medial compartment osteoarthritis; Total knee replacement; Unicompartmental knee replacement; Equipoise; Expertise
Posterior reversible encephalopathy syndrome (PRES) is an uncommon pathology characterized by the acute onset of headache, vomiting, altered consciousness, seizures and focal neurological deficits. It was initially described in the setting of hypertension, uremia and immunosuppression. In the last decade there have been emerging reports of PRES in patients with advanced human immunodeficiency virus (HIV)-infection in the presence of hypertension, dialysis, hypercalcaemia and two opportunistic infections: blastomycosis and tuberculosis (TB).
Here we present the case of a 54 year old male being treated for disseminated varicella zoster virus (VZV) and vasculopathy in the setting of HIV infection who acutely deteriorated to the point of requiring intubation. His clinicoradiological diagnosis was of PRES and he subsequently improved within 72 h with supportive management. Serial neuroimaging correlated with the clinical findings. The pathogenesis of PRES is poorly understood but is thought to stem from vasogenic oedema either as a result of loss of endothelial integrity and transudate of fluid across the blood–brain barrier, or secondary to vasospasm resulting in tissue oedema in the absence of infarction. How HIV infection impacts on this model is unclear. It is possible the HIV infection causes endothelial dysfunction and disruption of the blood–brain barrier that may be further exacerbated by infections in the central nervous system.
The phenomenon of PRES in advanced HIV is an important clinical entity for both physicians and critical care doctors to recognize firstly given its potential mortality but also because of its favourable prognosis and reversibility with supportive care and treatment of underlying causes.
PRES; HIV; VZV; MRI; Encephalopathy; Vasculopathy
To evaluate the morphological changes of the parotid glands in patients treated with intensity-modulated radiotherapy (IMRT) for nasopharyngeal and oropharyngeal tumors and the correlations with parotid function.
Ten patients with nasopharyngeal and oropharyngeal tumors treated with IMRT between May 2009 and January 2010 at Hokkaido University Hospital were included in this study. In the morphological assessment of the parotid glands, the sizes and computed tomography (CT) numbers of the bilateral parotid glands before and after IMRT with CT were calculated. For functional assessment of the parotid glands, we conducted the Saxon test and used a visual analog scale (VAS) for xerostomia evaluation.
Reductions in saliva secretion were observed in the patients treated with IMRT for nasopharyngeal and oropharyngeal tumors, and there was a significant correlation between the reduction in saliva secretion and the VAS. The reductions in the parotid gland size and CT number were larger on the ipsilateral side than on the contralateral side. The reduction in saliva secretion was not significantly correlated with the reduction in parotid gland size, but was significantly correlated with the reduction in CT number.
Morphological and functional changes of the parotid glands were observed after IMRT for nasopharyngeal and oropharyngeal tumors, and preservation of the contralateral parotid glands was only partly achieved. Among the morphological changes of the parotid glands, the CT number may be considered a predictor of parotid function after radiotherapy.
Intensity-modulated radiotherapy (IMRT); Parotid gland; Nasopharyngeal and oropharyngeal tumors; Morphological and functional changes
Since 2005, Australian clinicians were advised to undertake quarterly syphilis testing for all sexually active HIV-positive men who have sex with men (MSM). We describe differences in syphilis testing frequency among HIV-positive MSM by clinic testing policies since this recommendation.
Three general practices, two sexual health clinics and two hospital HIV outpatient clinics provided data on HIV viral load and syphilis testing from 2006–2010. Men having ≥1 viral load test per year were included; >95% were MSM. We used Chi-2 tests to assess changes in syphilis testing frequency over time, and differences by clinic testing policy (opt-out, opt-in and risk-based).
The proportion of men having HIV viral loads with same-day syphilis tests increased from 37% in 2006 to 63% in 2007 (p<0.01) and 68–69% thereafter. In 2010, same-day syphilis testing was highest in four clinics with opt-out strategies (87%, range:84–91%) compared with one clinic with opt-in (74%, p = 0.121) and two clinics with risk-based strategies (22%, range:20–24%, p<0.01). The proportion of men having ≥3 syphilis tests per year increased from 15% in 2006 to 36% in 2007 (p<0.01) and 36–38% thereafter. In 2010, the proportion of men having ≥3 syphilis tests in a year was highest in clinics with opt-out strategies (48%, range:35–59%), compared with opt-in (39%, p = 0.121) and risk-based strategies (8.4%, range:5.4–12%, p<0.01).
Over five years the proportion of HIV-positive men undergoing syphilis testing at recommended frequencies more than doubled, and was 5–6 times higher in clinics with opt-out and opt-in strategies compared with risk-based policies.
Combination antiretroviral therapy (cART) has greatly improved the life expectancy of people living with HIV (PLHIV). Our study aims to project the life expectancy of PLHIV in a resource-rich setting in the context of the currently available antiretroviral treatments.
Patient antiretroviral treatment data were sourced from an observational cohort of 3,434 predominantly male (94.2%) PLHIV in Australia over the period 1997–2010. These data were analysed in a computer simulation model to calculate the distribution of time until exhaustion of all treatment options and expected effect on mortality. Standardised mortality ratios were used to simulate expected survival before and after treatment exhaustion.
We estimated that the median time until exhaustion of currently available treatment options is 45.5 years (IQR 34.0–61.0 years). However, 10% of PLHIV are expected to exhaust all currently available cART options after just 25.6 years. PLHIV who start currently available cART regimens at age 20 years are expected to live to a median age of 67.4 (IQR 53.2–77.7) years. This is a substantial improvement on no cART (27.7 [IQR 23.8–32.0] years) but is still substantially less than the median general population mortality age (82.2 [IQR 74.0–87.8] years). The life expectancy gap between PLHIV and the general population is greatest for those infected at younger ages.
As treatment options are exhausted, a substantial difference in life expectancy between PLHIV and the general population could be expected even in resource-rich settings, particularly for people who acquire HIV at a younger age or who are currently highly treatment experienced.
antiretroviral therapy; HIV; life expectancy; survival
Meta-analysis; Rosiglitazone/Pioglitazone; Lipoatrophy; HIV; HAART