Machine learning applied to atopic dermatitis transcriptome reveals distinct therapy-dependent modification of the keratinocyte immunophenotype.

BACKGROUND: Atopic dermatitis (AD) arises from a complex interaction between an impaired epidermal barrier, environmental exposures, and the infiltration of T helper (Th)1/Th2/Th17/Th22 T cells. Transcriptomic analysis has advanced our understanding of gene expression in cells and tissues. However, molecular quantitation of cytokine transcripts does not predict the importance of a specific pathway in AD or cellular responses to different inflammatory stimuli. OBJECTIVES: To understand changes in keratinocyte transcriptomic programmes in human cutaneous disease during development of inflammation and in response to treatment. METHODS: We performed in silico deconvolution of the whole-skin transcriptome. Using co-expression clustering and machine-learning tools, we resolved the gene expression of bulk skin (seven datasets, n = 406 samples), firstly, into keratinocyte phenotypes identified by unsupervised clustering and, secondly, into 19 cutaneous cell signatures of purified populations from publicly available datasets. RESULTS: We identify three unique transcriptomic programmes in keratinocytes - KC1, KC2 and KC17 - characteristic of immune signalling from disease-associated Th cells. We cross-validate those signatures across different skin inflammatory conditions and disease stages and demonstrate that the keratinocyte response during treatment is therapy dependent. Broad-spectrum treatment with ciclosporin ameliorated the KC17 response in AD lesions to a nonlesional immunophenotype, without altering KC2. Conversely, the specific anti-Th2 therapy, dupilumab, reversed the KC2 immunophenotype. CONCLUSIONS: Our analysis of transcriptomic signatures in cutaneous disease biopsies reveals the effect of keratinocyte programming in skin inflammation and suggests that the perturbation of a single axis of immune signal alone may be insufficient to resolve keratinocyte immunophenotype abnormalities.

Osteonecrosis following treatment for childhood acute lymphoblastic leukaemia: The Southampton Children's Hospital experience.

Purpose: To determine the prevalence of osteonecrosis (ON) in children following treatment of acute lymphoblastic leukaemia (ALL), characterise these cases and review treatment methods. Methods: All children diagnosed and treated for ALL between 01 January 2003 and 31 December 2013 at our centre were retrospectively reviewed. Logistic regression was used to investigate risk factors for ON occurrence. Results: Of 235 children treated for ALL, 48/235 (20.4%) children suffered musculoskeletal symptoms necessitating radiological investigation. A total of 13 (5.5%) had MRI-diagnosed ON, with a median diagnosis time of 12 months (interquartile range 10 to 14) following initiation of chemotherapy.ON affected 40 joints in 13 children. The most commonly involved joints were hips (14 joints in eight patients) and knees (12 joints in seven patients).Older age at ALL diagnosis was associated with significantly increased risk of development of ON per year (odds ratio 1.35, 95% confidence interval 1.17 to 1.57, p < 0.001).Eight children underwent at least one surgical intervention. Joint arthroplasty was undertaken in nine joints of four children at a mean age of 18.3 years. All patients who underwent hip arthroplasty had previously received core decompression, with a mean time of 27.8 months (18 to 33) between treatments. Conclusions: ON is a significant complication of ALL treatment. Our results suggest risk stratification for development of ON by age, and targeted monitoring of high-risk joints is possible. ON treatment is varied with little evidence base.

A case-control study of elective hip surgery among HIV-infected patients: exposure to systemic glucocorticoids significantly increases the risk.

OBJECTIVES: This was a cross-sectional study with a nested case-control analysis among a cohort of HIV-infected adults aiming to explore the prevalence of and risk factors for elective hip surgery (total hip arthroplasty and resurfacing). METHODS: Cases were identified from the out-patient database of HIV-infected adults attending one tertiary hospital service. For each case, five controls from the same database matched by age, gender and ethnicity were identified. From the case notes, information about demographic factors, HIV factors and risk factors for hip surgery attributable to osteoarthritis or avascular necrosis (body mass index, lipids, alcohol, comorbidities and treatment with oral glucocorticoids) was extracted. RESULTS: Among the cohort of 1900 HIV-infected out-patients, 13 cases (12 male) who had undergone hip surgery [0.7%; 95% confidence interval (CI) 0.3-1.1%] were identified, with a median age of 47 years. Eleven of the 13 cases (85%) were Caucasian and seven of the 13 were in stage 3 of HIV infection. Fewer of the cases were in the asymptomatic stage of infection compared with controls [odds ratio (OR) for stage 2 or 3 infection 4.0; 95% CI 0.8-18.5]. Ever having used oral glucocorticoids was highly significantly associated with elective hip surgery (OR 44.6; 95% CI 5.7-347.7). CONCLUSIONS: Among this young cohort, the prevalence of elective hip surgery was 0.7%, with the median age at surgery being 47 years. Ever having been exposed to systemic glucocorticoids was highly significantly associated with elective hip surgery, suggesting that the principal mechanism underlying the need for surgery was avascular necrosis. There may be an increased need for elective hip surgery associated with HIV infection.

FOXO3 expression during colorectal cancer progression: biomarker potential reflects a tumour suppressor role.

BACKGROUND: In previous studies, the Forkhead/winged-helix-box-class-O3 (FOXO3) transcription factor has displayed both tumour suppressive and metastasis-promoting properties.To clarify its role in human colorectal cancer (CRC) progression, we examined in vivo FOXO3 expression at key points of the metastatic cascade. METHODS: Formalin-fixed paraffin-embedded resection specimens from normal colon, adenomas, primary CRC specimens of different pathological stage and CRC specimens with matched liver metastases were used to generate three separate custom-designed tissue microarray (TMA) representations of metastatic progression. Triplicate cores, immunostained for FOXO3 were scored semiquantitatively by two investigators. RESULTS: The FOXO3 expression is significantly reduced in CRC specimens compared with normal tissue, and progressive FOXO3 downregulation is associated with advancing pathological stage. In addition, recurrent stage I/II primary tumours show a significantly lower FOXO3 expression compared with stage-matched non-recurrent tumours. When stratified according to high and low FOXO3 expression, mean disease-free survival in the low-expressing group was 28 months (95% CI 15.8-50.6) compared with 64 months (95% CI 52.9-75.4) in the high-expressing group. CONCLUSION: We have demonstrated an association between low FOXO3 expression and CRC progression in vivo using purpose-designed TMAs. Forkhead/winged-helix-box-class-O3 may represent a novel biomarker of nodal and distant disease spread with clinical utility in CRC.

Is lung function associated with bone mineral density? Results from the Hertfordshire Cohort Study.

UNLABELLED: Given limited information available regarding associations between lung function and bone mineral density among healthy subjects, we undertook these analyses in the Hertfordshire Cohort Study. Forced expiratory volume in 1 s (FEV(1)), forced vital capacity (FVC) and FEV(1)/FVC were not associated with bone mineral density at any site; associations with bone mineral content were removed by adjustment for body size. PURPOSE: There is limited information available regarding the association between lung function and bone mineral density among healthy elderly subjects. We addressed this issue in the Hertfordshire Cohort Study. METHODS: From the above cohort, 985 subjects (496 men and 489 women) aged 60-72 years were recruited. All subjects underwent bone density measurements using dual energy X-ray absorptiometry and lung function tests using standardised spirometry. Chronic obstructive pulmonary disease (COPD) was defined as a FEV(1)/FVC ratio

Long-term outcome following total knee arthroplasty: a controlled longitudinal study.

OBJECTIVES: To assess long-term outcome and predictors of prognosis following total knee arthroplasty (TKA) for osteoarthritis. METHODS: We followed-up 325 patients from 3 English health districts approximately 6 years after TKA, along with 363 controls selected from the general population. Baseline data, collected by interview and examination, included age, sex, comorbidity, body mass index (BMI), functional status and preoperative radiographic severity of osteoarthritis. Functional status at follow-up was assessed by postal questionnaire. Predictors of change in physical function were analysed by linear regression. RESULTS: Between baseline and follow-up, patients reported an improvement of 6 points in median Short Form 36 Health Survey (SF-36) physical function score, whereas in controls there was a deterioration of 14 points (p<0.001). Median SF-36 vitality score declined by 10 points in patients and 5 points in controls (p = 0.005), while their median SF-36 mental health scores improved by 12 and 13 points, respectively (p = 0.2). The improvement in physical function was smaller in patients who were obese than in patients who were non-obese, but compared favourably with a substantial decline in the physical function of obese controls. Better baseline physical function and older age predicted worse changes in physical function in patients and controls. Improvement in physical function tended to be greater in patients with more severe radiological disease of the knee, and was less in those who reported pain at other joint sites at baseline. CONCLUSIONS: Improvements in physical function following TKA for osteoarthritis are sustained beyond 5 years. The benefits are apparent in patients who are obese as well as non-obese, and there seems no justification for withholding TKA from obese patients solely on the grounds of their body mass index.

A randomised controlled trial of tidal irrigation vs corticosteroid injection in knee osteoarthritis: the KIVIS Study.

OBJECTIVES: Patients with knee osteoarthritis (OA) often suffer pain that is not fully controlled by analgesics and often require intra-articular therapies. The aim of this study was to compare the benefits of intra-articular corticosteroid injections (CSIs) and tidal irrigation (TI) in patients with OA of the knee. METHODS: We performed a dual-centre, single blind, randomised, parallel group trial comparing TI and CSI. Patients with knee OA were randomised to either irrigation using a 3.2mm arthroscope under local anaesthesia or an intra-articular injection of 40 mg triamcinolone acetonide and 1% lidocaine. Patients were followed for 6 months. The primary outcome measure was the Western Ontario and McMaster Universities OA Index total pain score (visual analogue scale, VAS). RESULTS: One hundred and fifty patients were recruited of whom 71 received TI and 79 CSI. In both treatment groups, over 80% of patients reported improvement at 2 and 4 weeks. After this time, the benefit of CSI decreased whereas that of TI was maintained: at 26 weeks the pain relief afforded by TI was significantly greater than that of CSI. At 26 weeks 29% of the CSI group reported improvement vs 64% of the TI group (P<0.001). Patients with a knee effusion responded better to both treatments, however, this was most apparent for CSI. Patients with less severe radiographic OA also obtained the greatest improvement from both treatments. CONCLUSION: Both procedures lead to significant short-term pain relief of at least 4 weeks, however, TI displayed a significantly greater duration of benefit. Patients with effusions and milder radiographic change obtained the best response to treatment.

How common is repetitive strain injury?

OBJECTIVE: Statistics from Labour Force Surveys are widely quoted as evidence for the scale of occupational illness in Europe. However, occupational attribution depends on whether participants believe their health problem is caused or aggravated by work, and personal beliefs may be unreliable. The authors assessed the potential for error for work-associated arm pain. METHODS: A questionnaire was mailed [corrected] to working-aged adults, randomly chosen from five British general practices. They were asked about: occupational activities; mental health; self-rated health; arm pain; and beliefs about its causation. Those in work (n = 1769) were asked about activities likely to cause arm pain, from which the authors derived a variable for exposure to any "arm-straining" occupational activity. The authors estimated the relative risk (RR) from arm-straining activity, using a modified Cox model, and derived the population attributable fraction (PAF). They compared the proportion of arm pain cases reporting their symptom as caused or made worse by work with the calculated PAF, overall and for subsets defined by demographic and other characteristics. RESULTS: Arm pain in the past year was more common in the 1143 subjects who reported exposure to arm-straining occupational activity (RR 1.2, 95% CI 1.1 to 1.5). In the study sample as a whole, 53.9% of 817 cases reported their arm pain as work-associated, whereas the PAF for arm-straining occupational activity was only 13.9%. The ratio of cases reported as work-related to the calculated attributable number was substantially higher below 50 years (5.4) than at older ages (3.0) and higher in those with worse self-rated and mental health. CONCLUSIONS: Counting people with arm pain which they believe to be work-related can overestimate the number of cases attributable to work substantially. This casts doubt on the validity of a major source of information used by European governments to evaluate their occupational health strategies.

Population-based cohort study of incident and persistent arm pain: role of mental health, self-rated health and health beliefs.

To investigate whether somatising tendency, low mood and poor self-rated health (SRH) predict incident arm pain, and whether these factors and beliefs about causation and prognosis predict symptom persistence, we conducted an 18-month postal follow-up in 1798 working-aged subjects, sampled from the registers of five British general practices. At baseline questions were asked about pain in the arm (lasting >or=1day in the prior 12months), mental health (Short-Form 36 (SF-36MH)), somatising tendency (the Brief Symptom Inventory (BSI)), SRH, and beliefs about causation and prognosis. At follow-up we asked about arm pain in the last four weeks, and whether it had been present on >or=14days. Associations with incidence and persistence were explored using logistic regression. The 1256 participants (70% response) comprised 613 free of, and 643 with, arm pain initially. Among the former, 21% reported new pain at follow-up, while 53% of the latter reported symptom persistence. The odds of both incident and persistent arm pain were significantly raised (1.7- to 4-fold) in the least vs. most favourable bands of SF-36MH, BSI and SRH. Even stronger associations were found for arm pain on >or=14days. Persistent pain was significantly more common among those who attributed their pain to work or stress, and in those who expected symptoms still to be a problem in 12months. Thus, SRH and mental health indices were strong predictors of incident and persistent arm pain in adults from the community, while persistence was also predicted by beliefs about causation and prognosis.

Variation in the matrix metalloproteinase-3, -7, -12 and -13 genes is associated with functional status in rheumatoid arthritis.

As matrix metalloproteinases (MMPs) play an important role in rheumatoid arthritis, we investigated whether variation in MMP genes was associated with functional disability in rheumatoid arthritis patients. A cohort of patients with seropositive rheumatoid arthritis were recruited and genotyped for the MMP1-1607 1G > 2G, MMP3-1612 5A > 6A, MMP7-153C > T, MMP7-181G > A, MMP12-82A > G and MMP13-77A > G polymorphisms. Genotypes were then analysed in relation to functional disability assessed by Steinbrocker index and Health Assessment Questionnaire (HAQ) score. We detected an association between the MMP13-77 A > G polymorphism and Steinbrocker index, with patients of the A/A genotype having higher score than patients of the A/G or G/G genotype (P = 0.005), and the association remained significant after adjusting for age, sex, erythrocyte sedimentation rate, presence of erosive disease, Ritchie score, prednisolone therapy and years of diagnosis (P = 0.003). We also observed a relationship of Steinbrocker index with the MMP3-1612 5A > 6A, MMP7-181 A > G and MMP12-82A > G polymorphisms (P = 0.082, P = 0.037 and P = 0.045). No association was detected between the MMP1-1607 1G > 2G and MMP7-153C > T polymorphisms and either Steinbrocker index or HAQ score. These results suggest that MMP3, MMP7, MMP12 and MMP13 genotypes may play a role in determining functional status of rheumatoid arthritis.

Does knee pain in the community behave like a regional pain syndrome? Prospective cohort study of incidence and persistence.

OBJECTIVES: To investigate whether knee pain in the community behaves like a regional pain syndrome, determined by its association with mental health, self-rated health (SRH) and beliefs about prognosis. METHODS: An 18-month postal follow-up was conducted in 1798 working-aged subjects, sampled from the community. At baseline questions were asked about pain in the knee lasting > or =1 day in the previous 12 months, mental health (Short-Form 36), somatising tendency (elements of the Brief Symptom Inventory), SRH and concern about 12-month prognosis. At follow-up we asked about knee pain during the last 4 weeks, and whether it had been present for > or =14 days or prescription-treated. Associations with incidence and persistence were explored using logistic regression. RESULTS: The 1256 participants (70% response) comprised 468 with knee pain at baseline and 788 without. Among the former, 49% had persistent knee pain at follow-up, while among the latter, 15% reported new symptoms. Incident prescription-treated knee pain was strongly associated with all of the mental health variables and with SRH. The odds of knee pain persisting were significantly raised in the least versus most favourable bands of somatising tendency and SRH, and persistence was also significantly more common among those who at baseline were concerned that they would still have a problem in 12 months. CONCLUSIONS: Our observations support the hypothesis that knee pain in the community shares risk factors in common with other non-specific regional pain syndromes.

A multicentre randomized controlled trial of epidural corticosteroid injections for sciatica: the WEST study.

OBJECTIVE: To determine the effectiveness and predictors of response to lumbar epidural corticosteroid injections (ESI) in patients with sciatica. We performed a 12-month, multicentre, double-blind, randomized, placebo-controlled, parallel-group trial in four secondary pain-care clinics in the Wessex Region. METHODS: Two hundred and twenty-eight patients with a clinical diagnosis of unilateral sciatica of 1-18 months' duration were randomized to either three lumbar ESIs of triamcinolone acetonide or interligamentous saline injections at intervals of 3 weeks. The main outcome measure was the Oswestry low back pain disability questionnaire (ODQ). RESULTS: At 3 weeks, the ESI group demonstrated a transient benefit over the placebo group (patients achieving a 75% improvement in ODQ, 12.5 vs 3.7%; number needed to treat, 11.4). No benefit was demonstrated from 6 to 52 weeks. ESIs did not improve physical function, hasten return to work or reduce the need for surgery. There was no benefit of repeated ESIs over single injection. No clinical predictors of response were found. At the end of the study the majority of patients still had significant pain and disability regardless of intervention. CONCLUSIONS: In this pragmatic study, ESIs offered transient benefit in symptoms at 3 weeks in patients with sciatica, but no sustained benefits in terms of pain, function or need for surgery. Sciatica is a chronic condition requiring a multidisciplinary approach. To fully investigate the value of ESIs, they need to be evaluated as part of a multidisciplinary approach.

The changing use of disease-modifying anti-rheumatic drugs in individuals with rheumatoid arthritis from the United Kingdom General Practice Research Database.

OBJECTIVES: To describe the use of disease-modifying anti-rheumatic drugs (DMARDs) in the treatment of rheumatoid arthritis (RA) and changing trends in their use. METHODS: We used the General Practice Research Database (GPRD) to describe DMARD use by patients with RA identified using ICD-9 codes. The GPRD is a UK national database containing records of more than 7 million individuals from 683 general practices. Subjects were studied between 1987 and 2002. The prevalence and duration of individual DMARD use and changing trends in DMARD use were investigated. RESULTS: Thirty-four thousand three hundred and sixty-four patients with RA were identified. Only 17,115 (50%) individuals were prescribed at least one DMARD during the study period. The most commonly prescribed DMARD over the study period was sulphasalazine (46.3%) and then methotrexate (31.4%). Use of methotrexate has increased 17-fold (1.8% of all DMARD prescriptions in 1988 to 30% in 2002) whereas use of gold has fallen (13.2% to 2.3%). Analysis of DMARD persistence using Kaplan-Meier survival curves showed the methotrexate use persisted significantly longer than other DMARDs with an estimated median of 8.1 yr. Prednisolone was used in up to 50% of RA patients in any one year and has remained fairly constant throughout the study period. CONCLUSIONS: Large numbers of individuals with a clinical diagnosis of RA identified from a large primary care database are not receiving DMARDs. This work suggests that many individuals with RA have not been treated appropriately and this may have major long-term consequences on joint damage and general health.

Knee disorders in the general population and their relation to occupation.

BACKGROUND: Hospital based studies of occupational risk factors for knee disorders are complicated by the possibility of selective referral to hospital of people whose work is made difficult by their symptoms. AIMS: To explore the extent of such bias and to assess the association of meniscal injury with occupational activities. METHODS: A questionnaire was mailed to a community sample of 2806 men aged 20-59 years in southern England. This asked about lifetime occupational and sporting activities, and any history of knee symptoms lasting 24 hours or longer. Rates of hospital referral were compared in symptomatic men according to their occupational activities. In a nested case-control investigation, the occupational activities of 67 men who reported meniscectomy were compared with those of 335 controls. RESULTS: Among 1404 men who responded to the questionnaire, the lifetime prevalence of knee symptoms was 54%, and in 70% of cases the symptoms had started suddenly, usually while playing sport. Symptomatic men whose work entailed kneeling or squatting were more likely to be referred to an orthopaedic surgeon than the average (28% and 31% versus 24%), especially if they experienced locking of the knee (69% and 73% versus 43%). In the nested case-control study, meniscectomy was associated with playing soccer and work that involved regular kneeling or squatting. CONCLUSIONS: Results suggest that hospital referral for knee symptoms is influenced to some extent by patients' occupational activities. Playing soccer is confirmed as a strong risk factor for knee cartilage injury.

Pain tolerance in upper limb disorders: findings from a community survey.

AIMS: To test the hypothesis that non-specific upper limb pain arises from altered pain perception with reduced tolerance of sensory stimuli. METHODS: Subjects undergoing clinical examination as part of a community based survey of upper limb disorders were invited to return for an assessment of pain tolerance. A standardised algorithm was used to classify the 94 participants according to whether they had specific upper limb disorders (n = 22), non-specific arm pain (n = 15), or no arm pain (n = 57). Pain tolerance was assessed at three anatomical sites in each arm in response to electrocutaneous stimulation with alternating currents up to a maximum of 10 mA at three frequencies (5, 250, and 2,000 Hz). A proportional odds model was used to compare pain tolerance thresholds according to sex, age, and diagnosis. RESULTS: Women were less tolerant of pain than men (OR 0.13) and tolerance also declined with age (OR for one year increase in age 0.97). After allowance for sex and age, there was no indication that pain tolerance was lower in subjects with non-specific arm pain than in those with specific upper limb disorders or those who had no arm pain. CONCLUSIONS: The study hypothesis was not supported. However, before the hypothesis is dismissed, it should be tested further in patients with more severe and disabling arm pain.

Reliability of the Southampton examination schedule for the diagnosis of upper limb disorders in the general population.

BACKGROUND: Epidemiological research in the field of soft tissue neck and upper limb disorders has been hampered by the lack of an agreed system of diagnostic classification. In 1997, a United Kingdom workshop agreed consensus definitions for nine of these conditions. From these criteria, an examination schedule was developed and validated in a hospital setting. OBJECTIVE: To investigate the reliability of this schedule in the general population. METHODS: Ninety seven adults of working age reporting recent neck or upper limb symptoms were invited to attend for clinical examination consisting of inspection and palpation of the upper limbs, measurement of active and passive ranges of motion, and clinical provocation tests. A doctor and a trained research nurse examined each patient separately, in random order and blinded to each other's findings. RESULTS: Between observer repeatability of the schedule was generally good, with a median kappa coefficient of 0.66 (range 0.21 to 0.93) for each of the specific diagnoses considered. CONCLUSION: As expected, the repeatability of tests is poorer in the general population than in the hospital clinic, but the Southampton examination schedule is sufficiently reproducible for epidemiological research in the general population.

Intrauterine exposure to a maternal low protein diet reduces adult bone mass and alters growth plate morphology in rats.

Epidemiological studies suggest that poor growth during fetal life and infancy is associated with decreased bone mass in adulthood. However, theses observations have not, to date, been corroborated in animal models. To address this issue we evaluated the influence of maternal protein restriction on bone mass and growth plate morphology among the adult offspring, using a rat model. Maternal protein restriction resulted in a reduction in bone area and BMC, but not BMD, among the offspring in late adulthood. The widened epiphyseal growth plate in the protein-restricted offspring is compatible with the programming of cartilage and bone growth by maternal nutrition in early life.

Knee osteoarthritis and obesity.

OBJECTIVES: To assess the risk of knee osteoarthritis (OA) attributable to obesity, and the interactions between obesity and other established causes of the disorder. METHODS: We performed a population-based case-control study in three health districts of England (Southampton, Portsmouth and North Staffordshire). A total of 525 men and women aged 45 y and over, consecutively listed for surgical treatment of primary knee OA, were compared with 525 controls matched by age, sex and family practitioner. RESULTS: Relative to a body mass index (BMI) of 24.0-24.9 kg/m(2), the risk of knee OA increased progressively from 0.1 (95% CI 0.0-0.5) for a BMI<20 kg/m(2) to 13.6 (95% CI 5.1-36.2) for a BMI of 36 kg/m(2) or higher. If all overweight and obese people reduced their weight by 5 kg or until their BMI was within the recommended normal range, 24% of surgical cases of knee OA (95% CI 19-27%) might be avoided. As a risk factor for knee OA obesity interacted more than additively with each of Heberden's nodes, earlier knee injury and meniscectomy. In comparison with subjects of normal weight, without Heberden's nodes, and with no history of knee injury, people with a combination of obesity, definite Heberden's nodes and previous knee injury had a relative risk of 78 (95% CI 17-354). CONCLUSIONS: Our findings give strong support to public health initiatives aimed at reducing the burden of knee OA by controlling obesity. People undergoing meniscectomy or with a history of knee injury might be a focus for targeted advice.

The Southampton examination schedule for the diagnosis of musculoskeletal disorders of the upper limb.

OBJECTIVES: Following a consensus statement from a multidisciplinary UK workshop, a structured examination schedule was developed for the diagnosis and classification of musculoskeletal disorders of the upper limb. The aim of this study was to test the repeatability and the validity of the newly developed schedule in a hospital setting. METHOD: 43 consecutive referrals to a soft tissue rheumatism clinic (group 1) and 45 subjects with one of a list of specific upper limb disorders (including shoulder capsulitis, rotator cuff tendinitis, lateral epicondylitis and tenosynovitis) (group 2), were recruited from hospital rheumatology and orthopaedic outpatient clinics. All 88 subjects were examined by a research nurse (blinded to diagnosis), and everyone from group 1 was independently examined by a rheumatologist. Between observer agreement was assessed among subjects from group 1 by calculating Cohen's kappa for dichotomous physical signs, and mean differences with limits of agreement for measured ranges of joint movement. To assess the validity of the examination, a pre-defined algorithm was applied to the nurse's examination findings in patients from both groups, and the sensitivity and specificity of the derived diagnoses were determined in comparison with the clinic's independent diagnosis as the reference standard. RESULTS: The between observer repeatability of physical signs varied from good to excellent, with kappa coefficients of 0.66 to 1.00 for most categorical observations, and mean absolute differences of 1.4 degrees -11.9 degrees for measurements of shoulder movement. The sensitivity of the schedule in comparison with the reference standard varied between diagnoses from 58%-100%, while the specificities ranged from 84%-100%. The nurse and the clinic physician generally agreed in their diagnoses, but in the presence of shoulder capsulitis the nurse usually also diagnosed shoulder tendinitis, whereas the clinic physician did not. CONCLUSION: The new examination protocol is repeatable and gives acceptable diagnostic accuracy in a hospital setting. Examination can feasibly be delegated to a trained nurse, and the protocol has the benefit of face and construct validity as well as consensus backing. Its performance in the community, where disease is less clear cut, merits separate evaluation, and further refinement is needed to discriminate between discrete pathologies at the shoulder.