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ObjectivesLumbar disc disease is a known cause of back pain. Increasingly it is thought that cam morphology of the hip may have a causal role in development of lumbar disc disease. The aim of this study was to describe the morphology of the hip and investigate the association of cam morphology with lumbar disc disease observed on MRI in elite rowers.MethodsCross-sectional observational study of 20 elite rowers (12 male, 8 female, mean age 24.45, SD 2.1). Assessment included clinical examination, questionnaires, 3T MRI scans of the hips and lumbar spine. Alpha angle of the hips and Pfirrmann score of lumbar discs were measured.Results85% of rowers had a cam morphology in at least one hip. Alpha angle was greatest at the 1 o’clock position ((bone 70.9 (SD 16.9), cartilage 71.4 (16.3)). 95% of the group were noted to have labral tears, but only 50% of the group had history of groin pain. 85% of rowers had at least one disc with a Pfirrmann score of 3 or more and 95% had a history of back pain. A positive correlation was observed between the alpha angle and radiological degenerative disc disease (correlation coefficient=3.13, p=0.012). A negative correlation was observed between hip joint internal rotation and radiological degenerative disc disease (correlation coefficient=−2.60, p=0.018).ConclusionsRowers have a high prevalence of labral tears, cam morphology and lumbar disc disease. There is a possible association between cam morphology and radiological lumbar degenerative disc disease, however, further investigation is required.

Resolution of inflammation is poorly understood in Achilles tendon disorders. Herein, we investigated the bioactive lipid mediator profiles of tendon‐derived stromal cells isolated from patients with Achilles tendinopathy (AT) or Achilles rupture (AR) under baseline and IL‐1β–stimulated conditions. We also determined whether incubating these cells with 2 of the mediators produced by tendon‐derived stromal cells, 15‐epi‐Lipoxin A4 (15‐epi‐LXA4) or maresin (MaR)‐1, moderated their proinflammatory phenotype. Under baseline conditions, AT cells showed concurrent increased levels of proinflammatory eicosanoids and proresolving mediators compared with AR cells. IL‐1β treatment induced profound prostaglandin E2 release in AR compared with AT cells. Incubation of IL‐1β treated AT and AR tendon‐derived stromal cells in 15‐epi‐LXA4 or MaR1 reduced proinflammatory eicosanoids and potentiated the release of proresolving mediators. These mediators also induced specialized proresolving mediator (SPM) biosynthetic enzymes arachidonate lipoxygenase (ALOX) 12 and ALOX15 and up‐regulated the proresolving receptor ALX compared with vehicle‐treated cells. Incubation in 15‐epi‐LXA4 or MaR1 also moderated the proinflammatory phenotype of AT and AR cells, regulating podoplanin, CD90, signal transducer and activator of transcription (STAT)‐1, IL‐6, IFN regulatory factor (IRF) 5, and TLR4 and suppressed c‐Jun N‐terminal kinase 1/2/3, Lyn, STAT‐3, and STAT‐6 Phosphokinase signaling. In summary, we identify proresolving mediators that are active in AT and AR and propose SPMs, including 15‐epi‐LXA4 or MaR1, as a potential strategy to counterregulate inflammatory processes in these cells.—Dakin, S. G., Colas, R. A., Newton, J., Gwilym, S., Jones, N., Reid, H. A. B., Wood, S., Appleton, L., Wheway, K., Watkins, B., Dalli, J., Carr, A. J. 15‐Epi‐LXA4 and MaR1 counter inflammation in stromal cells from patients with Achilles tendinopathy and rupture.

Background Osteoarthritis (OA) is a chronic joint disease, with increasing global burden of disability and healthcare utilisation. Recent meta-analyses have shown a range of effects of OA on mortality, reflecting different OA definitions and study methods. We seek to overcome limitations introduced when using aggregate results by gathering individual participant-level data (IPD) from international observational studies and standardising methods to determine the association of knee OA with mortality in the general population. Methods Seven community-based cohorts were identified containing knee OA-related pain, radiographs, and time-to-mortality, six of which were available for analysis. A two-stage IPD meta-analysis framework was applied: (1) Cox proportional hazard models assessed time-to-mortality of participants with radiographic OA (ROA), OA-related pain (POA), and a combination of pain and ROA (PROA) against pain and ROA-free participants; (2) hazard ratios (HR) were then pooled using the Hartung–Knapp modification for random-effects meta-analysis. Findings 10,723 participants in six cohorts from four countries were included in the analyses. Multivariable models (adjusting for age, sex, race, BMI, smoking, alcohol consumption, cardiovascular disease, and diabetes) showed a pooled HR, compared to pain and ROA-free participants, of 1.03 (0.83, 1.28) for ROA, 1.35 (1.12, 1.63) for POA, and 1.37 (1.22, 1.54) for PROA. Discussion Participants with POA or PROA had a 35–37% increased association with reduced time-to-mortality, independent of confounders. ROA showed no association with mortality, suggesting that OA-related knee pain may be driving the association with time-to-mortality. Funding Versus Arthritis Centre for Sport, Exercise and Osteoarthritis and Osteoarthritis Research Society International.

OBJECTIVE: Population-based osteoarthritis (OA) cohorts provide vital data on risk factors and outcomes of OA, however the methods to define OA vary between cohorts. We aimed to provide recommendations for combining knee and hip OA data in extant and future population cohort studies, in order to facilitate informative individual participant level analyses.METHOD: International OA experts met to make recommendations on: 1) defining OA by X-ray and/or pain; 2) compare The National Health and Nutrition Examination Survey (NHANES)-type OA pain questions; 3) the comparability of the Western Ontario & McMaster Universities Osteoarthritis Index (WOMAC) scale to NHANES-type OA pain questions; 4) the best radiographic scoring method; 5) the usefulness of other OA outcome measures. Key issues were explored using new analyses in two population-based OA cohorts (Multicenter Osteoarthritis Study; MOST and Osteoarthritis Initiative OAI).RESULTS: OA should be defined by both symptoms and radiographs, with symptoms alone as a secondary definition. Kellgren and Lawrence (K/L) grade ≥2 should be used to define radiographic OA (ROA). The variable wording of pain questions can result in varying prevalence between 41.0% and 75.4%, however questions where the time anchor is similar have high sensitivity and specificity (91.2% and 89.9% respectively). A threshold of 3 on a 0-20 scale (95% CI 2.1, 3.9) in the WOMAC pain subscale demonstrated equivalence with the preferred NHANES-type question.CONCLUSION: This research provides recommendations, based on expert agreement, for harmonising and combining OA data in existing and future population-based cohorts.

Anterior mid-tibial cortex stress fractures (ATCSF) are uncommon and notoriously challenging to treat. They are termed high risk due to their predilection to prolonged recovery, nonunion and complete fracture. Early diagnosis is essential to avoid progression and reduce fracture complications. Imaging plays a key role in confirming the diagnosis. Magnetic resonance imaging (MRI) is accepted as the gold standard modality due to its high accuracy and nonionizing properties. This report describes three cases of ATCSFs in recreational athletes who had positive radiographic findings with no significant MRI changes. Two athletes had multiple striations within their tibias. Despite the radiographic findings, their severity of symptoms were low with mild or no tenderness on examination. Clinicians should be mindful that the ATCSFs may not present with typical acute stress fracture symptoms. We recommend that plain radiographs should be used as the first line investigation when suspecting ATCSFs. Clinicians should be aware that despite MRI being considered the gold standard imaging modality, we report three cases where the MRI was unremarkable, whilst radiographs and computed tomography confirmed the diagnosis. We urge clinicians to continue to use radiographs as the first line imaging modality for ATCSFs and not to directly rely on MRI. Those who opt directly for MRI may be falsely reassured causing a delay in diagnosis.

Physical activity (PA) is increasingly recognised as an important factor within studies of osteoarthritis (OA). However, subjective methods used to assess PA are highly variable and have not been developed for use within studies of OA, which creates difficulties when comparing and interpreting PA data in OA research. The aim of this study was, therefore, to gain expert agreement on the appropriate methods to harmonise PA data among existing population cohorts to enable the investigation of the association of PA and OA. The definition of PA in an OA context and methods of harmonization were established via an international expert consensus meeting and modified Delphi exercise using a geographically diverse committee selected on the basis of individual expertise in physical activity, exercise medicine, and OA. Agreement was met for all aims of study: (1) The use of Metabolic Equivalent of Task (MET) minutes per week (MET-min/week) as a method for harmonising PA variables among cohorts; (2) The determination of methods for treating missing components of MET-min/week calculation; a value will be produced from comparable activities within a representative cohort; (3) Exclusion of the domain of occupation from total MET-min/week; (4) The need for a specific measure of joint loading of an activity in addition to intensity and time, in studies of diseases, such as OA. This study has developed a systematic method to classify and harmonise PA in existing OA cohorts. It also provides minimum requirements for future studies intending to include subjective PA measures. Electronic supplementary material The online version of this article (doi:10.1007/s00296-017-3672-y) contains supplementary material, which is available to authorized users.

Purpose: To describe physical activity (PA) levels and motivators and barriers to PA amongst haemodialysis (HD) patients and to identify an appropriate approach to increasing their PA. Methods: A cross-sectional mixed methods study conducted in a tertiary and satellite HD unit. One hundred and one participants aged 18 years and over, receiving regular HD for at least four months, were recruited. Patients with recent hospital admission or acute cardiac event were excluded. Participants completed health status (EQ-5D-3L™) and activity (Human Activity Profile (HAP)) questionnaires. A subgroup was invited to wear accelerometers and wearable cameras to measure PA levels and capture PA episodes, to inform subsequent semi-structured interviews on motivators and barriers. Semi-structured interviews were analysed using the framework method informed by constructs of the Health Belief Model. Results: 98/101 completed the study (66 males, 32 females). For 68/98 participants, adjusted activity scores from the HAP indicated “impaired” levels of PA; for 67/98 participants, the EQ-5D-3L indicated problems with mobility. Semi-structured interviews identified general (fear of falls, pain) and disease specific barriers (fatigue) to PA. Motivators included tailored exercise programmes and educational support from health care professionals. Conclusions: Participants indicated a need for co-development with healthcare professionals of differentiated, targeted exercise interventions.Implications for rehabilitationHealthcare professionals should encourage and motivate haemodialysis patients to participate in physical activity (PA).As part of this approach, there is a need to increase patient knowledge of safe beneficial exercise activities and help individuals identify and overcome barriers.To allow for individualised approaches, clinical interventions should focus on other community activities that patients can do outside the dialysis clinic setting and utilise existing networks such as the British Renal Society Rehabilitation Network.The dialysis clinic provides professionals the opportunity to monitor and motivate patients.Relevant education is needed for staff about the benefits of PA and how to engage patients and their carers in safe and effective approaches. Healthcare professionals should encourage and motivate haemodialysis patients to participate in physical activity (PA). As part of this approach, there is a need to increase patient knowledge of safe beneficial exercise activities and help individuals identify and overcome barriers. To allow for individualised approaches, clinical interventions should focus on other community activities that patients can do outside the dialysis clinic setting and utilise existing networks such as the British Renal Society Rehabilitation Network. The dialysis clinic provides professionals the opportunity to monitor and motivate patients. Relevant education is needed for staff about the benefits of PA and how to engage patients and their carers in safe and effective approaches.

Objective To evaluate the incidence of undiagnosed celiac disease (CD) in patients presenting with bone stress injuries (BSI) to a NHS Sport and Exercise Medicine (SEM) clinic. Design Retrospective cohort study. Setting Single tertiary-level SEM clinic. Patient/participants One hundred consecutive patients with radiologically proven BSIs. Interventions Laboratory blood tests (LBT) can unmask underlying metabolic bone disorders. Anti-tissue transglutaminase antibody (TTG) testing has a high sensitivity and specificity for CD. In this SEM clinic, clinicians were encouraged to perform LBT including TTG, at time of diagnosis of BSI. A retrospective analysis of age, sex, fracture site, co-morbidities, TTG result, and subsequent investigations was performed. Main outcome measures The primary outcome was the number and percentage of patients with BSIs and either positive TTG (CD seropositivity) or a diagnosis of CD. Results Of the 100 patients with radiologically proven BSIs, 70% were female, and the mean age was 37 years (range 16-69). Eighty-five percent had the appropriate LBTs, of which 70% (60/85) were female, and the mean age was 37(16-69). Metatarsal (35%) and tibial (21%) were the most common BSIs. Anti-tissue transglutaminase antibody was performed in 85 patients. Two patients (2/85) had pre-existing CD and were excluded from incidence calculations. Five patients [5/83 (6%), mean age 38 years (28-57), 80% female] had a positive TTG, of whom 3 have subsequently had CD confirmed by endoscopic biopsy. Four patients with a positive TTG underwent dual-energy X-ray absorptiometry with osteopenia found in 3 (75%) cases. Conclusions In this cohort, the incidence of CD seropositivity was 6%, and the prevalence of biopsy-confirmed CD was 5%, approximately 5-fold higher than UK population estimates. Anti-tissue transglutaminase antibody screening for CD should be considered in all patients presenting with BSIs.

Introduction Stress fractures, fatigue-induced bone fractures caused by repetitive mechanical stress, are often multifactorial in nature and are associated with a number of metabolic bone disorders. Whilst the association between coeliac disease (CD) and osteoporosis is well-recognised, it is unclear whether an association between CD and stress fractures exists, with only rare case reports in the literature. This study aimed to examine the incidence of CD in a prospective cohort of patients presenting with stress fractures to a specialist NHS Sport and Exercise Medicine (SEM) clinic. Methods An analysis of a prospective cohort of 100 consecutive patients with radiologically-proven stress fractures who presented to a single tertiary UK SEM clinic was performed. Electronic health records were used to examine fracture site, comorbidities, tissue transglutaminase (TTG) result, biochemistry, haematinics, dual energy x-ray absorptiometry, and endoscopy findings. Results Seventy patients in the cohort were female (70%) and the mean age was 37 years (range 18–69). Two patients had pre-existing coeliac disease (2%). Coeliac serology was performed for 85 patients (85%), with 5 additional patients found to have a positive TTG (5% of cohort, 6% of those tested). CD was confirmed by endoscopic biopsy in three patients, with two not undergoing endoscopy locally due to their geographic location, giving a prevalence of CD in this cohort of 5–7%. The most common site of fracture was the metatarsals (5/7, 71%), with hallux sesamoid and fibula fractures detected in one patient each respectively. Six patients with possible or confirmed CD underwent DEXA. No patients had osteoporosis, with osteopenia (T-Score between -1.0 and -2.5) found in three patients (3/6, 50%). Coexistent vitamin and mineral deficiency were common in the CD patients (iron, 2/6 (33%); vitamin B12, 2/5 (40%); folate, 1/4 (25%); vitamin D, 2/6 (33%)). Conclusions In this cohort of patients with stress fractures, the prevalence of CD was between 5% and 7%, approximately 5-fold higher than general UK population estimates. Screening for CD with serological testing should be considered in all patients presenting with stress fractures. Stress fractures were not associated with osteoporosis in the patients with CD, and only 50% had osteopenia, suggesting that coeliac disease and the associated malabsorption leads to stress fracture via mechanisms separate from reduced bone density.

Knee osteoarthritis (KOA) is commonly defined by radiographic changes and knee pain. KOA has a multifactorial aetiology, but there are several well-recognised strong risk factors for the incidence of KOA. These include age, sex, body mass index (BMI), previous injuries, bone density, smoking and pre-existing hand osteoarthritis (HOA). Factors associated with mild systemic and synovial inflammation are potential markers for KOA incidence. The hypothesis for this research was that selected markers associated with synovial inflammation and/or variables linked with metabolic syndrome (MetS) are prognostic for KOA incidence. Self-reported knee stiffness, serum markers associated with knee synovitis, and variables associated with MetS were selected as potential risk factors for KOA incident.

Objective It is unclear whether the association between osteoarthritis (OA) and metabolic syndrome (MetS) varies with the site of the affected joint and the presence of pain. Our aim was to describe the association between MetS and radiographic OA (ROA) affecting the knee or the hand in the presence or absence of concurrent joint pain. Methods Cross-sectional data of 952 women, aged 45-65 years from from the Chingford study, a population-based longitudinal cohort of middle-aged women initiated in 1988-1989 in London (UK), was analysed. MetS was defined using the National Cholesterol Education Program Treatment Panel III criteria. Data was collected on components of MetS: waist circumference, triglycerides, high-density lipoprotein (HDL), blood pressure and blood glucose. The outcome was four knee and hand OA groups: painful ROA, ROA only, pain only and neither ROA nor pain (reference category). Multinomial logistic regression models adjusted for age and body mass index (BMI) were used to evaluate the effect of presence of MetS and its individual components on OA subgroups for knee and hand separately. Results 952 eligible women, aged 45-65 years was analysed. A significant association was observed between the presence and the number of MetS with painful knee ROA when adjusted for age; however, this association disappeared when BMI was included in the model. In contrast, the presence and the number of MetS were associated with painful interphalangeal (IPJ) OA after adjusting for both age and BMI. Four out of the five MetS components, including triglycerides, HDL-c, hypertension and glucose, were associated with painful IPJ OA. Conclusions MetS is associated with painful IPJ OA but not with knee OA once BMI is taking into consideration. Further attention to MetS and OA at different sites is needed to understand the metabolic phenotype in OA.

The aim of this study is to describe the prevalence of joint-specific self-reported pain, physician-diagnosed osteoarthritis (OA), and joint replacement in former elite English cricketers, and to analyse the associations of self-reported severe joint injury with these musculoskeletal conditions at the hip, knee, ankle, shoulder, and spine.

BackgroundRecent investigation of human tissue and cells from positional tendons such as the rotator cuff has clarified the importance of inflammation in the development and progression of tendon disease. These mechanisms remain poorly understood in disease of energy-storing tendons such as the Achilles. Using tissue biopsies from patients, we investigated if inflammation is a feature of Achilles tendinopathy and rupture.MethodsWe studied Achilles tendon biopsies from symptomatic patients with either mid-portion tendinopathy or rupture for evidence of abnormal inflammatory signatures. Tendon-derived stromal cells from healthy hamstring and diseased Achilles were cultured to determine the effects of cytokine treatment on expression of inflammatory markers.ResultsTendinopathic and ruptured Achilles highly expressed CD14+ and CD68+ cells and showed a complex inflammation signature, involving NF-κB, interferon and STAT-6 activation pathways. Interferon markers IRF1 and IRF5 were highly expressed in tendinopathic samples. Achilles ruptures showed increased PTGS2 and interleukin-8 expression. Tendinopathic and ruptured Achilles tissues expressed stromal fibroblast activation markers podoplanin and CD106. Tendon cells isolated from diseased Achilles showed increased expression of pro-inflammatory and stromal fibroblast activation markers after cytokine stimulation compared with healthy hamstring tendon cells.ConclusionsTissue and cells derived from tendinopathic and ruptured Achilles tendons show evidence of chronic (non-resolving) inflammation. The energy-storing Achilles shares common cellular and molecular inflammatory mechanisms with functionally distinct rotator cuff positional tendons. Differences seen in the profile of ruptured Achilles are likely to be attributable to a superimposed phase of acute inflammation and neo-vascularisation. Strategies that target chronic inflammation are of potential therapeutic benefit for patients with Achilles tendon disease.

Background Obesity is associated with an increased risk of developing osteoarthritis (OA), even in non-weight bearing joints. High levels of adipose tissue-associated inflammation may explain this association. Sources of data and areas of debate Published evidence looking at the associations between components of Metabolic Syndrome (MetS) and knee, hip or hand OA and the higher mortality described with knee OA. Emerging points Development of MetS and OA shares a relationship with adipose tissue-associated inflammation. This review supports this inflammatory pathway being part of the shared mechanism behind obesity as a risk factor for OA and the recently described OA-associated increased mortality. Timely areas for development In an era of an obesity epidemic, this review identifies a need for well-designed cohort studies assessing early metabolic changes in populations at high risk of OA and MetS, and to identify risk factors for increased mortality in patients with OA.

Aim: This descriptive review aimed to assess the characteristics and methodological quality of economic evaluations of cardiac rehabilitation (CR) programs according to updated economic guidelines for healthcare interventions. Recommendations will be made to inform future research addressing the impact of a physical exercise component on cost-effectiveness. Methods: Electronic databases were searched for economic evaluations of exercise-based CR programs published in English between 2000 and 2014. The Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement was used to review the methodological quality of included economic evaluations. Results: Fifteen economic evaluations met the review inclusion criteria. Assessed study characteristics exhibited wide variability, particularly in their economic perspective, time horizon, setting, comparators and included costs, with significant heterogeneity in exercise dose across interventions. Ten evaluations were based on randomised controlled trials (RCTs) spanning 6-24 months but often with weak or inconclusive results; two were modelling studies; and the final three utilised longer time horizons of 3.5-5 years from which findings suggest that long-term exercise-based CR results in lower costs, reduced hospitalisations and a longer cumulative patient lifetime. None of the 15 articles met all the CHEERS quality criteria, with the majority either fully or partially meeting a selection of the assessed variables. Conclusion: Evidence exists supporting the cost-effectiveness of exercise-based CR for cardiovascular disease patients. However, variability in CR program delivery and weak consistency between study perspective and design limits study comparability and therefore the accumulation of evidence in support of a particular exercise regime. The generalisability of study findings was limited due to the exclusion of patients with comorbidities as would typically be found in a real-world setting. The use of longer time-horizons would be more comparable with a chronic condition and enable economic assessments of the long-term effects of CR. As none of the articles met recent reporting standards for the economic assessment of healthcare interventions, it is recommended that future studies adhere to such guidelines.

In the general population, physical activity is associated with improved health outcomes. However, long-term sports participation may be associated with adverse outcomes, particularly at the elite level. The aims of this study were to assess morbidity and health-related quality of life (HrQoL) amongst former rugby players, compared to an age-standardised general population sample. A cross-sectional study of former elite, male, rugby players (n = 259) was undertaken, and standardised morbidity ratios (SMR) calculated, assessing morbidity prevalence relative to English Longitudinal Study of Aging participants (ELSA, n = 5186). HrQoL, measured using the EQ-5D, was compared to a Health Survey for England (HSE, n = 2981) sample. In SMR analyses of participants aged 50+, diabetes was significantly lower amongst former players, (0.28, 95% CI 0.11–0.66), whereas osteoarthritis (4.00, 95% CI 3.32–4.81), joint replacement (6.02, 95% CI 4.66–7.77), osteoporosis (2.69, 95% CI 1.35–5.38), and anxiety (2.00, 95% CI 1.11–3.61) were significantly higher. More problems in HrQoL were reported amongst former players within the domains of mobility (p

IntroductionCam morphology is a strong risk factor for the development of hip pain and osteoarthritis. It is increasingly thought to develop in association with intense physical activity during youth; however, the aetiology remains uncertain. The study aim was to characterise the effect of physical activity on morphological hip development during adolescence.MethodsCross-sectional study of individuals aged 9–18 years recruited from Southampton Football Club Academy (103 male) with an age-matched control population (52 males and 55 females). Assessments included questionnaires and 3 Tesla MRI of both hips. Alpha angle, epiphyseal extension and epiphyseal tilt were measured on radial images.ResultsAlpha angle and epiphyseal extension increased most rapidly between ages 12 and 14 years. Soft-tissue hypertrophy at the femoral head-neck junction preceded osseous cam morphology and was first evident at age 10 years. The greatest increase and highest absolute values of alpha angle and epiphyseal extension were colocalised at 1 o’clock. Maximum alpha angles were 6.7 degrees greater in males than females (p=0.005). Compared with individuals who play no regular sport, alpha angles were 4.0 degrees higher in individuals who play sport for a school or club (p=0.041) and 7.7 degrees higher in individuals competing at a national or international level (p=0.035). There was no association with leg dominance .ConclusionsSporting activity during adolescence is strongly associated with the development of cam morphology secondary to epiphyseal hypertrophy and extension with a dose-response relationship. Males participating in competitive sport are at particularly elevated risk of developing cam morphology and secondary hip pathology.

Background Radiographic knee osteoarthritis (RKOA) is associated with the knee pain. However, more than half of the middle-aged individuals with RKOA will report no concurrent knee pain. Specific matrix metalloproteinases (MMPs) generated protein fragments have been associated with knee synovitis and suggested as specific neo-epitope biomarkers of joint remodelling. Objectives The aim of the study was to evaluate the association between MMP-derived neo-epitope biomarkers measured in serum, and future incidence of either painful RKOA or RKOA without pain, in a cohort of middle-aged women with no RKOA at baseline. Methods 585 participants (mean age 53.2, mean BMI 25.1) from the Chingford 1000 Women Study Chingford Women Study had serum biomarker levels of MMP- degraded of CRP (CRPM), collagen type II (C2M) and collagen type III (C3M) measured at year 2 or 3 of the study. All participants had a Kellgren Lawrence (KL) score of 0 in both knees at baseline. Ten years following the recruitment, incidence of RKOA was determined as KL ≥2 and painful RKOA was defined as the presence of pain on any number of days in the preceding month in the knee with RKOA. Log-transformed normalised biomarker levels were utilised in separate logistic regression models adjusted for age. Outcomes were defined as either RKOA without pain or painful RKOA. Further analyses were performed adjusting for both age and BMI. Results 24.6% of women developed RKOA during 10 years after the recruitment, but only 8.9% of developed RKOA associated with concurrent knee pain. After adjusting for age, statistically significant positive associations were found between C3M and CRPM and the risk of developing painful RKOA with odds ratio (OR) =3.4 (95% confidence interval (CI): 1.4 to 8.2), and OR=2.5 (95% CI: 1.2, 5.2) respectively. After adjusting for age and BMI, only C3M was positively associated with risk of developing painful RKOA with OR=3.2 (95% CI: 1.3, 7.8). Conclusions In a population of middle-aged women without knee osteoarthritis, an MMP generated neo-epitope of collagen III previously linked with knee synovitis (C3M) can independently identify high-risk individuals for developing painful RKOA. These findings indicate that targeting MMP activity may be a promising therapeutic strategy in well-targeted populations. Disclosure of Interest C. Thudium Employee of: Nordic Bioscience, S. Kluzek: None declared, J. Newton: None declared, T. Spector: None declared, D. Hart: None declared, M. Karsdal: None declared, A. Bay-Jensen: None declared, N. Arden: None declared

The aim of this study was to determine if the fast bowling action in cricket, during which the front leg experiences about twice the loading of the back leg, causes a clinically significant difference in the normalized medial or lateral tibial cartilage volume of the higher loaded front versus the back leg.

AimStress fracture aetiology is often multifactorial and laboratory blood tests (LBT) can unmask underlying metabolic bone risk factors and disorders. Coeliac disease (CD) is associated with low bone mineral density and an increased risk of fractures.1 In addition, there are rare reports of occult CD presenting with stress fractures.2 Anti-tissue transglutaminase antibody (TTG) testing has a high sensitivity and specificity for CD and is used as a screening test.3 This report examines the incidence of undiagnosed CD in patients presenting with stress fractures to a Sport and Exercise Medicine (SEM) clinic.MethodsA retrospective analysis of 100 consecutive patients with radiologically proven stress fractures presenting to a single tertiary NHS SEM clinic was performed. Age, gender, fracture site, co-morbidities, TTG result and subsequent investigations were examined. Records were reviewed to confirm LBT, including TTG, had been performed at the time of diagnosis.ResultsSeventy patients (70%) were female and mean age was 37 years (range 18–69). Metatarsal (35%) and tibial (21%) fractures were most common. TTG was performed in 85 patients. Two patients were excluded due to pre-existing CD. Five patients (5/83 (6%), mean age 38 years (28–57), 80% female) had a positive TTG; three of whom had CD confirmed by endoscopic biopsy and two are awaiting investigation. Four patients with a positive TTG underwent dual energy X-ray absorptiometry, with osteopenia (T-Score between −1.0 and −2.5) found in 75% of cases, although only one had a Z-score less than -2.0.ConclusionIn this cohort, the incidence of undiagnosed CD was between 3.6% to 6%, with a prevalence between 5% to 7%, approximately 5-fold higher than UK population estimates. We recommend that TTG screening should be performed in all patients presenting with stress fractures to identify underlying CD. Further work is required to confirm this association and elucidate potential underlying mechanisms.ReferencesHeikkilä K, Pearce J, Mäki M, et al. Celiac disease and bone fractures: a systematic review and meta-analysis. J Clin Endocrinol Metab 2015;100(1):25–34.Gilbody J, Trevett M. Coeliac disease presenting with bilateral fibular stress fractures. Foot Ankle Surg 2009;15:96–100.3. Downey L, Houten R, Murch S, Longson D, Group GD. Recognition, assessment, and management of coeliac disease: summary of updated NICE guidance. BMJ 2015;351:h4513.

We would like to thank Gao et al for their interest in our paper ‘Painful knee but not hand osteoarthritis is an independent predictor of mortality over 23 years follow-up of a population-based cohort of middle-aged women’. Gao et al highlighted a number of issues related to a discordance between pain and radiographic changes and sensitivity of the pain assessment. Although a single definition of knee osteoarthritis (KOA) remains elusive, the presence of knee pain is the main symptom of knee osteoarthritis(OA)(2-4) and there is still a strong relationship between pain and ROA. (5, 6) Notwithstanding this, a substantial number of patients with radiographic knee osteoarthritis (ROA) are asymptomatic. Although OA is the most common ‘source’ of knee pain in ROA, it is true, as pointed out by Gao et al. that many other diagnoses may be judged to account for a patient’s symptoms including bursitis, tendinopathies and overuse injuries. In this cohort of middle aged to elderly women, we feel that these alternative causes will not be prevalent. We defined pain as the presence of side-specific knee pain in the preceding month, and painful radiographic KOA as knee specific pain and presence of ROA. We have performed additional analyses to further address the queries of Gao at al.

There is a marked lack of research into the long-term health of former elite cricketers. The aim of this study is to analyse the risk of long-term health conditions in former elite cricketers by comparing the prevalence of their chronic conditions to a general population sample.

ObjectiveTo describe the effectiveness of intravenous pamidronate in the treatment of resistant osteitis pubis (OP) in athletes.MethodsEight consecutive high-level amateur athletes attending a Sport and Exercise Medicine clinic with refractory OP and bone marrow oedema (BME) of the symphysis pubis on magnetic resonance imaging (MRI) were treated with intravenous pamidronate infusions. Patients above 60 kg in weight received 60 mg intravenous pamidronate and those below 60 kg received 30 mg. Patients were offered a second dose after a 3-month interval if symptoms had not improved sufficiently. Primary outcome measure was return to sport. Secondary outcome measures were pain scores on a 0–10 scale and a rating of overall improvement pre- and post-infusion.ResultsMean symptom duration was 19 months. Five patients rated themselves as ‘significantly improved’ and one had ‘some improvement’. All five patients who reported a ‘significant improvement’ returned to sport. Pain scores improved: (1) at rest (...

Objective Hip pain and injury as a result of activity can lead to the development of early hip osteoarthritis (OA) in susceptible individuals. Our understanding of the factors that increase susceptibility continues to evolve. The ability to clearly identify individuals (and cohorts) with activity-related hip pain who are at risk of early hip OA is currently lacking. The purpose of this study was to gain expert consensus on which key clinical measures might help predict the risk of early hip OA in individuals presenting with activity-related hip pain. The agreed measures would constitute a standardised approach to initial clinical assessment to help identify these individuals. Methods This Dephi study used online surveys to gain concordance of expert opinion in a structured process of ‘rounds’. In this study, we asked ‘What outcome measures are useful in predicting hip OA in activity-related hip pain?’ The Delphi panel consisted of experts from sport and exercise medicine, orthopaedics, rheumatology, physiotherapy and OA research. Results The study identified key clinical measures in the history, examination and investigations (plain anteroposterior radiograph and femoroacetabular impingement views) that the panel agreed would be useful in predicting future risk of hip OA when assessing activity-related hip pain. The panel also agreed that certain investigations and tests (eg, MR angiography) did not currently have a role in routine assessment. There was a lack of consensus regarding the role of MRI, patient-reported outcome measures (PROMs) and certain biomechanical and functional assessments. Conclusions We provide a standardised approach to the clinical assessment of patients with activity-related hip pain. Assessment measures rejected by the Delphi panel were newer, more expensive investigations that currently lack evidence. Assessment measures that did not reach consensus include MRI and PROMs. Their role remains ambiguous and would benefit from further research.

To assess whether joint pain or radiographic osteoarthritis (ROA) of the knee and hand is associated with all-cause and disease-specific mortality in middle-aged women. Methods: Four subgroups from the prospective community-based Chingford Cohort Study were identified based on presence/absence of pain and ROA at baseline: (Pain−/ROA−; Pain+/ROA−; Pain−/ROA+; Pain+/ROA+). Pain was defined as side-specific pain in the preceding month, while side-specific ROA was defined as Kellgren–Lawrence grade ≥2. All-cause, cardiovascular disease (CVD) and cancer-related mortality over the 23-year follow-up was based on information collected by the Office for National Statistics. Associations between subgroups and all-cause/cause-specific mortality were assessed using Cox regression, adjusting for age, body mass index, typical cardiovascular risk factors, occupation, past physical activity, existing CVD disease, glucose levels and medication use. Results: 821 and 808 women were included for knee and hand analyses, respectively. Compared with the knee Pain−/ROA− group, the Pain+/ROA− group had an increased risk of CVD-specific mortality (HR 2.93 (95% CI 1.47 to 5.85)), while the knee Pain+/ROA+ group had an increased HR of 1.97 (95% CI 1.23 to 3.17) for all-cause and 3.57 (95% CI 1.53 to 8.34) for CVD-specific mortality. We found no association between hand OA and mortality. Conclusion: We found a significantly increased risk of all-cause and CVD-specific mortality in women experiencing knee pain with or without ROA but not ROA alone. No relationship was found between hand OA and mortality risk. This suggests that knee pain, more than structural changes of OA is the main driver of excess mortality in patients with OA.

than in 2002 (41%), P= 0.027. ABPM recordings showed significantly fewer undiagnosed hypertensive individuals in 2012 (14%) that in 2002 (28%), P< 0.001. Significantly more hypertensive individuals were optimally treated in 2012, (44%) versus (19%), P < 0.001. Minimum and mean systolic BP were significantly lower in the 2012 cohort, but maximum systolic BP and diastolic BP did not differ. Use of ACE inhibitor, angiotensin receptor blockers and diuretics had significantly increased over the 10-year interval. Patient reported rates of falls, dizziness and syncope had not risen significantly. Ischaemic heart disease was significantly less common in the 2012 cohort, P< 0.05. Conclusion: Hypertension in older people is better recognised and more effectively managed now than 10 years ago. This has not been associated with a significant change in rates of falls, dizziness or syncope.

Aims Economic evaluations provide a useful comparative approach for considering costs and consequences on patient outcomes, thus providing a foundation for effective policy and decision making.1 2 This descriptive review aims to better understand how economic evaluations of cardiac rehabilitation (CR) services are conducted to inform future research addressing the impact of a physical exercise component on cost-effectiveness. Methods Electronic databases were searched for economic evaluations of exercise-based CR programs published in English between 2000 and 2014. The methodological quality of included economic evaluations was reviewed using criteria taken from the Consolidated Health Economic Evaluation Reporting Standards (CHEERS) statement.3 Results Fifteen economic studies met the eligibility criteria but exhibited wide variability in study perspective, time horizon, setting, comparators and included costs, with significant heterogeneity for exercise dose between interventions. Ten evaluations were based on randomised controlled trials (RCTs) with time horizons between 6–24 months, but which largely produced weak or inconclusive results. Excluding two modelling studies, only three studies utilised longer time horizons (3.5–5 years), and findings suggest exercise-based CR leads to lowered costs, reduced rehospitalisation9s and longer cumulative lifetime in the long-term. Conclusions Variability in CR program delivery and exercise dose along with weak consistency between study perspective and included costs makes it difficult to compare cost and health outcomes between studies and accumulate evidence in support of a particular exercise regime. The dominance of RCTs with their extensive patient selectivity process and exclusion of comorbid patients questions whether cost-effectiveness findings would translate to a real-world setting. The use of longer time horizons would be more compatible with a chronic condition and allow the long-term effects of exercise-based CR to be evaluated.

Self-reported pain questions are the established way to determine osteoarthritis (OA) related pain in population cohort studies, of which NHANES-type (National Health Nutrition Examination Survey) questions and WOMAC (Western Ontario and McMaster Universities Arthritis Index) are the most common. However, there is limited understanding of how wording variations relating to the duration of pain (i.e. most days in the month) and period of pain recall (i.e. in the last year) affect the prevalence and comparability of these questions. The aim of this research was to assess four common NHANES pain questions and to establish an equivalent threshold within the WOMAC pain subscale.

The aim of the study was to determine the prevalence and risk factors for HIV-associated fatigue in the era of highly active antiretroviral therapy (HAART).A cross-sectional survey of 100 stable HIV-infected out-patients was carried out. Severity of fatigue was measured using the Fatigue Impact Scale (FIS). Symptoms of orthostatic intolerance (dysautonomia) were evaluated using the Orthostatic Grading Scale (OGS). Data for HIV-infected patients were compared with those for 166 uninfected controls and 74 patients with chronic fatigue syndrome (CFS)/myalgic encephalomyelitis (encephalopathy) (ME).Ninety-one per cent of HIV-infected patients were on HAART and 78% had suppressed plasma HIV viral load (≤ 40 HIV-1 RNA copies/mL). Fifty-one per cent of HIV-infected patients reported excessive symptomatic fatigue (FIS ≥ 40), and 28% reported severe fatigue symptoms (FIS ≥ 80). The mean FIS score among HIV-infected patients was 50.8 [standard deviation (SD) 41.9] compared with 13.0 (SD 17.6) in uninfected control subjects, and 92.9 (SD 29.0) in CFS patients (P0.001 for comparison of HIV-infected patients and uninfected controls). Among HIV-infected patients, fatigue severity was not significantly associated with current or nadir CD4 lymphocyte count, HIV plasma viral load, or whether on HAART. Prior dideoxynucleoside analogue (d-drug) exposure (P = 0.016) and the presence of clinical lipodystrophy syndrome (P = 0.011) were associated with fatigue. Additionally, fatigue severity correlated strongly with symptomatic orthostatic intolerance (r = 0.65; P0.001).Fatigue is very common and often severe in HIV-infected out-patients, despite viral suppression and good immune function. In a subgroup of patients, prior d-drug exposure may contribute to fatigue, suggesting a metabolic basis. Dysautonomia may also drive fatigue associated with HIV infection, as in other chronic diseases, and CFS/ME, and should be further evaluated with the potential for a shared therapeutic approach.

to examine fatigue variability over time in chronic fatigue syndrome (CFS) and the effect of other symptoms on its predictability.longitudinal cohort study of patients with CFS (Fukuda criteria).specialist CFS clinical service.phase 1: 100 patients who participated in a study of CFS symptoms in 2005 were revisited in 2009. Phase 2: 25 patients completed fatigue diaries to address intra- and inter-day variability in perceived fatigue.phase 1: subjects completed fatigue impact scale (FIS), Epworth sleepiness scale (ESS), orthostatic grading scale (OGS) and hospital anxiety and depression scale (HADS). Changes in variables represented the differences between 2005 and 2009. Phase 2: subjects rated fatigue on a scale of 0 (no fatigue) to 10 (severe fatigue) four times a day for 5 weeks.symptom assessment tools were available in both 2005 and 2009 for 74% of patients. FIS and HADS depression (HAD-D) and anxiety (HAD-A) scores significantly improved during follow-up whereas ESS and OGS remained stable. FIS improved in 29/74 (39%) subjects, and by ≥ 10 points in 19 (26%). FIS worsened by ≥ 10 points in 33/74 (45%) subjects. On multivariate analysis, independent predictors of current fatigue (FIS in 2009) were FIS in 2005, HAD-D in 2009, OGS in 2009 and change in HAD-A. Reported fatigue was stable from week to week and from day to day. Patients reported higher fatigue in the morning (mean ± SD; 6.4 ± 2), becoming significantly lower at lunchtime (6.2 ± 2; P0.05) and increasing again to 7 ± 2 at bedtime.current fatigue is independently associated with current autonomic symptom burden, current depression and change in anxiety during follow-up. These findings have implications for targeted symptom management in CFS.

Aspirin is widely used to modify the risk of recurrent vascular events. It is, however, associated with increased upper gastrointestinal bleeding risk. The influence of Helicobacter pylori on this risk is uncertain.To determine the influence of H. pylori on upper gastrointestinal bleeding risk in patients taking aspirin.MEDLINE and EMBASE databases were searched. All studies providing data regarding H. pylori infection in adults taking aspirin and presenting with upper gastrointestinal bleeding were included.A total of 13 studies that included 1 case-control, 10 cohort studies and 2 randomized-controlled trials (RCTs) were analysed. The case-control study (n = 245) determined H. pylori to be a significant independent risk factor for upper gastrointestinal bleeding. The cohort studies were heterogeneous, varying in inclusion criteria, doses and duration of aspirin used, mode of H. pylori testing and causative GI pathology considered. Comprising 5465 patients, H. pylori infection was tested for in 163 (0.03%) aspirin users with upper gastrointestinal bleeding. The RCTs yielded no significant results.The current data are not sufficient to allow meta-analyses. The widely held belief that H. pylori is a risk factor for upper gastrointestinal bleeding in regular aspirin users is not supported by the very limited evidence available.

Anagrelide is a new therapeutic compound recently demonstrated to have a rapid and selective thrombocytopenic effect in humans. The effects of anagrelide were evaluated in plasma clot and liquid suspension cultures of optimally stimulated normal human peripheral blood megakaryocyte progenitors in order to determine the mechanism of its thrombocytopenic activity. In plasma clot cultures, at clinically relevant, therapeutic concentrations (5 to 50 ng/mL), anagrelide exerted no significant inhibitory effect on megakaryocyte colony numbers or colony size. Only at anagrelide concentrations of 10 to 500 times therapeutic doses did anagrelide inhibit megakaryocyte colony development: an anagrelide concentration of 5 micrograms/mL reduced colony numbers by 57% and colony size by 31%. In contrast, lower, therapeutic anagrelide concentrations exerted profound effects in liquid culture on megakaryocyte cytoplasmic maturation, size, and DNA content. When present for the entire 12-day culture duration, anagrelide induced left- shifted megakaryocyte maturation and reduced both megakaryocyte ploidy and megakaryocyte diameter. Anagrelide, at concentrations of 5 to 50 ng/mL, shifted the modal cultured megakaryocyte morphologic stage from III to II, reduced the model ploidy value from 16N to 8N, and decreased the mean megakaryocyte diameter by up to 22%, from 27.6 microns to 21.6 microns. Megakaryocyte diameter was significantly reduced in most instances, even when analyzed as a function of morphologic stage. When anagrelide was added to the cultures after 6- and 9-day delays (during the final 6 and 3 days, respectively, of culture), similar inhibitory effects on megakaryocyte maturation stage and ploidy distribution were observed. However, the magnitude of the left-shift in ploidy appeared to be less as the duration of anagrelide exposure was reduced. Conversely, megakaryocyte diameter was not significantly affected by the shorter 3- and 6-day anagrelide exposures. These data indicate that therapeutic concentrations of anagrelide influence primarily the postmitotic phase of megakaryocyte development, decreasing platelet production by reducing megakaryocyte size and ploidy, as well as by disrupting full megakaryocyte maturation. Inhibition of megakaryocyte diameter appears to require more prolonged anagrelide exposure than inhibition of maturation stage and ploidy. The molecular mechanisms responsible for the inhibitory effects of anagrelide on megakaryocytopoiesis remain to be defined.

Fatigue is a debilitating symptom which frequently impairs the quality of life of patients with primary biliary cirrhosis (PBC). Although the mechanisms underpinning fatigue in PBC remain unclear, there is an emerging consensus that CNS mechanisms play a key role. It has recently been shown that there is a strong association between abnormalities in sleep regulation, in particular excessive daytime somnolence, and fatigue severity in PBC. The CNS-acting drug modafinil has an established role in the treatment of excessive daytime somnolence in non-liver disease states.To explore, in an open label study, the responses of PBC patients suffering from significant daytime somnolence and associated fatigue to modafinil therapy.All patients in the series (n = 21) underwent daytime somnolence assessment using the Epworth Sleepiness Scale and PBC symptom assessment using the PBC-40, a multi-domain, disease specific, psychometrically robust quality of life measure. Modafinil was started at a dose of 100 mg/day and was titrated according to tolerability and response. Patients underwent repeat Epworth Sleepiness Scale and PBC-40 assessment after 2 months of treatment.Significant improvement was seen in Epworth Sleepiness Scale scores with modafinil therapy [15 +/- 3 vs. 8 +/- 6, P0.0005 (intention-to-treat analysis)]. An equally significant improvement in fatigue severity was also seen [PBC-40 fatigue domain score (46 +/- 6 vs. 34 +/- 12, P0.0001) (intention-to-treat analysis)].Open label modafinil therapy was associated, where tolerated by patients, with improvement in excessive daytime somnolence and associated fatigue in PBC. Further study in placebo-controlled trials is warranted.

Aspirin has a role in the prevention of cardiovascular and cerebrovascular disease, Alzheimer's dementia and several cancers. Encouraging all 50 year olds to take low-dose aspirin doubles their chances of living a healthy life into their nineties. The widespread use of aspirin, however, is limited as many older subjects are currently unable to take aspirin because of gastrointestinal side-effects. This review explores why gastrointestinal events occur with aspirin use and how a net benefit from prophylactic aspirin might be achieved in older subjects. It is suggested that, by understanding the age-related changes in upper gastrointestinal physiology and the mechanisms by which aspirin leads to the risk reductions associated with its use, it may be possible to direct interventions to improve tolerability in older subjects. This would allow greater numbers of older subjects to gain the benefits associated with aspirin use.

Peptic ulceration and Helicobacter pylori infection increase with advancing age. In the upper gastro-intestinal tract the first line of mucosal defence is the adherent mucus gel layer.We have examined, using a novel histological fixation technique, the thickness of the adherent mucus gel layer (1) in the gastric antrum and (2) in the duodenum in relation to advancing age and H. pylori status.The subjects had macroscopically normal stomach and duodenum at endoscopy. Measurement of the gastric antral mucus thickness was carried out on four antral biopsy specimens from within 2 cm of the pylorus (H. pylori positive n = 25, negative n = 21). The duodenal mucus thickness (D1) was measured from two biopsy specimens (H. pylori positive n = 7, negative n = 13). All specimens were snap frozen and cryostat sections stained using a modified PAS/AB stain.In all sections the mucus layer was continuous. In both duodenum and gastric antrum, the mucus thickness was not significantly different between H. pylori positive and H. pylori negative age-matched samples. In duodenum and gastric antrum from H. pylori negative subjects, there was no correlation between mucus thickness and age. However, in H. pylori positive subjects, there was a significant thinning of the adherent gastric antral mucus gel layer (p = 0.005, r = -0.54) and the duodenal mucus thickness (p0.001, r = -0.99) with advancing age.This study shows a significant thinning of the adherent mucus gel layer in H. pylori positive individuals, as stomach and duodenum age. In those without H. pylori, the mucus gel thickness is preserved in stomach and duodenum.

Investigations linking human megakaryocyte development and cell biology have been hindered by an inability to obtain large, relatively pure megakaryocyte cell preparations from in vitro stem cell cultures. We report here that such preparations can be generated from liquid cultures of normal human peripheral blood mononuclear cells stimulated by a serum source of megakaryocyte colony stimulating activity (Meg-CSA, the 0% to 60% ammonium sulfate protein fraction of aplastic canine serum). Adherent-depleted peripheral blood mononuclear cells are suspended at 5 x 10(5) to 10(6) cells/mL in supplemented liquid culture medium, platelet-poor human plasma 20% (vol/vol) and 1 to 2 mg/mL serum Meg-CSA protein. After 12 to 14 days of incubation, megakaryocytes constitute 3.0 +/- 2.9% (mean +/- SD, n = 8) of the unseparated cultured cell population. Megakaryocytes can be enriched by counterflow centrifugal elutriation to a purity of 58 +/- 14% (+/- SD) with a recovery of 13 +/- 7% and a viability of 67 +/- 19%. This algorithm results in the average isolation of approximately 3 x 10(5) enriched megakaryocytes from a 100-mL starting volume of peripheral blood. Cultured megakaryocytes exhibit normal light and ultrastructural morphology by Wright-Giemsa staining and electron microscopic analysis. After a 12-day culture interval, enriched megakaryocyte preparations exhibit morphologic stage distributions that are similar to normal human marrow. Stage distributions move rightward with culture duration indicating partial synchrony of megakaryocyte maturation. On cytospin preparations, megakaryocyte diameter averages 30.2 +/- 1.5 microns and increases with maturation stage. Flow cytometric analyses demonstrate the expression of platelet glycoproteins (GP) Ib and IIb/IIIa by the cultured megakaryocytes. The modal ploidy of the enriched cells at day 12 of culture is 16N and most remaining megakaryocytes are 8N or 32N. Liquid culture of serum Meg-CSA-stimulated human peripheral blood mononuclear cells represents a valuable investigative tool that should permit studies of human megakaryocyte biology that have not been possible in the past.

Electrical detection of a single donor level of interstitial boron at ${E}_{c}\ensuremath{-}0.13$ eV using novel photo---deep-level transient spectroscopy techniques is reported. Complementary behavior between this level and the acceptor level at ${E}_{c}\ensuremath{-}0.45$ eV establishes that the defect levels have negative-$U$ ordering. The donor level exhibits a large Poole-Frenkel effect which, when properly accounted for, provides a direct and unambiguous connection to the EPR-identified interstitial boron atom. This represents the first definitive indentification of negative-$U$ properties for a defect in any solid.

We present direct and unambiguous evidence that the donor levels of the silicon lattice vacancy are inverted in negative-U ordering, as originally suggested by Baraff et al. The second donor level, at Ev + 0.13 eV, lies above the first donor level, at Ev + 0.05 eV. First, we demonstrate that the Ev + 0.13 eV level is a donor state by the absence of the Poole-Frenkel effect in DLTS studies. Second, we describe a detailed EPR study of the reactions involving hole transfer via the valence band between the vacancy and the shallow aluminum acceptor. By monitoring the intensity of the V+ and Alos EPR signals, all aspects of the negative-U ordering appear to be confirmed.