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ObjectiveTo establish the feasibility of a multicentre randomised controlled trial to assess the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy in children with uncomplicated acute appendicitis.DesignFeasibility randomised controlled trial with embedded qualitative study to inform recruiter training to optimise recruitment and the design of a future definitive trial.SettingThree specialist paediatric surgery centres in the UK.PatientsChildren (aged 4–15 years) with a clinical diagnosis of uncomplicated acute appendicitis.InterventionsAppendicectomy or a non-operative treatment pathway (comprising broad-spectrum antibiotics and active observation).Main outcome measuresPrimary outcome measure was the proportion of eligible patients recruited. Secondary outcomes evaluated adherence to interventions, data collection during follow-up, safety of treatment pathways and clinical course.ResultsFifty per cent of eligible participants (95% CI 40 to 59) approached about the trial agreed to participate and were randomised. Repeated bespoke recruiter training was associated with an increase in recruitment rate over the course of the trial from 38% to 72%. There was high acceptance of randomisation, good patient and surgeon adherence to trial procedures and satisfactory completion of follow-up. Although more participants had perforated appendicitis than had been anticipated, treatment pathways were found to be safe and adverse event profiles acceptable.ConclusionRecruitment to a randomised controlled trial examining the effectiveness and cost-effectiveness of a non-operative treatment pathway compared with appendicectomy for the treatment of uncomplicated acute appendicitis in children is feasible.Trial registration numberNCT15830435.

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.

While non-operative treatment has emerged as an alternative to surgery for the treatment of uncomplicated acute appendicitis in children, comparative patient-centred outcomes are not well documented. We investigated these in a feasibility randomised trial. Of 57 randomised participants, data were available for 26. Compared with appendicectomy, children allocated to non-operative treatment reported higher short-term quality of life scores, shorter duration of requiring analgesia, more rapid return to normal activities and shorter parental absence from work. These preliminary data suggest differences exist in recovery profile and quality of life between these treatments that are important to measure in a larger RCT. Trial registration number isISRCTN15830435.

DESIGN: This randomised crossover trial compared nocturnal auto-adjusting continuous positive airway pressure (APAP) and nocturnal oxygen therapy (NOT) in adults and children with sickle cell anaemia, with patient acceptability as the primary outcome. Secondary outcomes included pulmonary physiology (adults), safety, and daily pain during interventions and washout documented using tablet technology.METHODS: Inclusion criteria were age > 8 years and the ability to use an iPad to collect daily pain data. Trial participation was 4 weeks; week 1 involved baseline data collection and week 3 was a washout between interventions, which were administered for 7 days each during weeks 2 and 4 in a randomised order. Qualitative interviews were transcribed verbatim and analysed for content using a funnelling technique, starting generally and then gaining more detailed information on the experience of both interventions. Safety data included routine haematology and median pain days between each period. Missing pain day values were replaced using multiple imputation.RESULTS: Ten adults (three female, median age 30.2 years, range 18-51.5 years) and eleven children (five female, median age 12 years, range 8.7-16.9 years) enrolled. Nine adults and seven children completed interviews. Qualitative data revealed that the APAP machine was smaller, easier to handle, and less noisy. Of 16 participants, 10 preferred APAP (62.5%, 95% confidence interval (CI) 38.6-81.5%). Haemoglobin decreased from baseline on APAP and NOT (mean difference -3.2 g/L (95% CI -6.0 to -0.2 g/L) and -2.5 g/L (95% CI -4.6 to 0.3 g/L), respectively), but there was no significant difference between interventions (NOT versus APAP, 1.1 (-1.2 to 3.6)). Pulmonary function changed little. Compared with baseline, there were significant decreases in the median number of pain days (1.58 for APAP and 1.71 for NOT) but no significant difference comparing washout with baseline. After adjustment for carry-over and period effects, there was a non-significant median difference of 0.143 (95% CI -0.116 to 0.401) days additional pain with APAP compared with NOT.CONCLUSION: In view of the point estimate of patient preference for APAP, and no difference in haematology or pulmonary function or evidence that pain was worse during or in washout after APAP, it was decided to proceed with a Phase II trial of 6 months APAP versus standard care with further safety monitoring for bone marrow suppression and pain.TRIAL REGISTRATION: ISRCTN46078697 . Registered on 18 July 2014.

BackgroundThe success of early dexamethasone therapy for hospitalised COVID-19 cases in treatment of Sars-CoV-2 infection may predominantly reflect its anti-inflammatory action against a hyperinflammation (HI) response. It is likely that there is substantial heterogeneity in HI responses in COVID-19.MethodsBlood CRP, ferritin, neutrophil, lymphocyte and platelet counts were scored to assess HI (HI5) and combined with a validated measure of generalised medical deterioration (NEWS2) before day 2. Our primary outcome was 28 day mortality from early treatment with dexamethasone stratified by HI5-NEWS2 status.FindingsOf 1265 patients, high risk of HI (high HI5-NEWS2) (n=367, 29.0%) conferred a strikingly increased mortality (36.0% vs 7.8%; Age adjusted hazard ratio (aHR) 5.9; 95% CI 3.6-9.8, pInterpretationThe HI5-NEWS2 measured at COVID-19 diagnosis, strongly predicts mortality at 28 days. Significant reduction in mortality with early dexamethasone treatment was only observed in the high risk group. Therefore, the HI5-NEWS2 score could be utilised to stratify randomised clinical trials to test whether intensified anti-inflammatory therapy would further benefit high risk patients and whether alternative approaches would benefit low risk groups. Considering its recognised morbidity, we suggest that early dexamethasone should not be routinely prescribed for HI5-NEWS2 low risk individuals with COVID-19 and clinicians should cautiously assess the risk benefit of this intervention.FundingNo external funding.

BackgroundAlthough non-operative treatment is known to be effective for the treatment of uncomplicated acute appendicitis in children, randomised trial data comparing important outcomes of non-operative treatment with those of appendicectomy are lacking.ObjectivesThe objectives were to ascertain the feasibility of conducting a multicentre randomised controlled trial comparing the clinical effectiveness and cost-effectiveness of a non-operative treatment pathway with appendicectomy for the treatment of uncomplicated acute appendicitis in children.DesignThis was a mixed-methods study, which included a feasibility randomised controlled trial, embedded and parallel qualitative and survey studies, a parallel health economic feasibility study and the development of a core outcome set.SettingThis study was set in three specialist NHS paediatric surgical units in England.ParticipantsChildren (aged 4–15 years) clinically diagnosed with uncomplicated acute appendicitis participated in the feasibility randomised controlled trial. Children, their families, recruiting clinicians and other health-care professionals involved in caring for children with appendicitis took part in the qualitative study. UK specialist paediatric surgeons took part in the survey. Specialist paediatric surgeons, adult general surgeons who treat children, and children and young people who previously had appendicitis, along with their families, took part in the development of the core outcome set.InterventionsParticipants in the feasibility randomised controlled trial were randomised to a non-operative treatment pathway (broad-spectrum antibiotics and active observation) or appendicectomy.Main outcome measuresThe primary outcome measure was the proportion of eligible patients recruited to the feasibility trial.Data sourcesData were sourced from NHS case notes, questionnaire responses, transcribed audio-recordings of recruitment discussions and qualitative interviews.ResultsOverall, 50% (95% confidence interval 40% to 59%) of 115 eligible patients approached about the trial agreed to participate and were randomised. There was high acceptance of randomisation and good adherence to trial procedures and follow-up (follow-up rates of 89%, 85% and 85% at 6 weeks, 3 months and 6 months, respectively). More participants had perforated appendicitis than had been anticipated. Qualitative work enabled us to communicate about the trial effectively with patients and families, to design and deliver bespoke training to optimise recruitment and to understand how to optimise the design and delivery of a future trial. The health economic study indicated that the main cost drivers are the ward stay cost and the cost of the operation; it has also informed quality-of-life assessment methods for future work. A core outcome set for the treatment of uncomplicated acute appendicitis in children and young people was developed, containing 14 outcomes. There is adequate surgeon interest to justify proceeding to an effectiveness trial, with 51% of those surveyed expressing a willingness to recruit with an unchanged trial protocol.LimitationsBecause the feasibility randomised controlled trial was performed in only three centres, successful recruitment across a larger number of sites cannot be guaranteed. However, the qualitative work has informed a bespoke training package to facilitate this. Although survey results suggest adequate clinician interest to make a larger trial possible, actual participation may differ, and equipoise may have changed over time.ConclusionsA future effectiveness trial is feasible, following limited additional preparation, to establish appropriate outcome measures and case identification. It is recommended to include a limited package of qualitative work to optimise recruitment, in particular at new centres.Future workPrior to proceeding to an effectiveness trial, there is a need to develop a robust method for distinguishing children with uncomplicated acute appendicitis from those with more advanced appendicitis, and to reach agreement on a primary outcome measure and effect size that is acceptable to all stakeholder groups involved.Trial registrationCurrent Controlled Trials ISRCTN15830435.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 10. See the NIHR Journals Library website for further project information.•Interventions Participants in the feasibility RCT were randomised to a non-operative treatment pathway (broadspectrum antibiotics and active observation) or appendicectomy.•Main outcome measuresPrimary outcome measure was the proportion of eligible patients recruited to the feasibility trial.•Data sourcesNHS casenotes, questionnaire responses, transcribed audio recordings of recruitment discussions and qualitative interviews•ResultsOverall, 50% (95%CI 40-59) of 115 eligible participants approached about the trial agreed to participate and were randomised. There was high acceptance of randomisation and good adherence to trial procedures and follow-up (follow rates of 89%, 85% and 85% at six weeks, three months and six months respectively). More participants had perforated appendicitis than had been anticipated. Qualitative work enabled us to: communicate about the trial effectively with patients and families; design and deliver bespoke training to optimise recruitment; and understand how to optimise design and delivery of a future trial. The health economic study, indicated that the main cost drivers are the ward stay cost and the cost of the operation, and has informed quality of life assessment methods for future work. A core outcome set for the treatment of uncomplicated acute appendicitis in children and young people was developed, containing 14 outcomes. There is adequate surgeon interest to justify proceeding to an effectiveness trial with 51% of those surveyed expressing a willingness to recruit with an unchanged trial protocol.•LimitationsSince the feasibility RCT was only performed in three centres we cannot guarantee successful recruitment across a larger number of sites. However, our qualitative work has informed a bespoke training package to facilitate this. Although survey results suggest adequate clinician interest to make a larger trial possible, actual participation may differ, and equipoise may have moved over time.•ConclusionsA future effectiveness trial is feasible following limited additional preparation to establish appropriate outcome measures and case identification. We recommend a limited package of qualitative work be included to optimise recruitment at new centres in particular.•Future workPrior to proceeding to an effectiveness trial we need to: develop a robust method for distinguishing children with uncomplicated acute appendicitis from those with more advanced appendicitis; reach agreement on a primary outcome measure and effect size that is acceptable to all stakeholder groups involved.

IntroductionPhysical rehabilitation delivered early following admission to the intensive care unit (ICU) has the potential to improve short-term and long-term outcomes. The use of supine cycling together with other rehabilitation techniques has potential as a method of introducing rehabilitation earlier in the patient journey. The aim of the study is to determine the feasibility of delivering the designed protocol of a randomised clinical trial comparing a protocolised early rehabilitation programme including cycling with usual care. This feasibility study will inform a larger multicentre study.Methods and analysis90 acute care medical patients from two mixed medical–surgical ICUs will be recruited. We will include ventilated patients within 72 hours of initiation of mechanical ventilation and expected to be ventilated a further 48 hours or more. Patients will receive usual care or usual care plus two 30 min rehabilitation sessions 5 days/week.Feasibility outcomes are (1) recruitment of one to two patients per month per site; (2) protocol fidelity with >75% of patients commencing interventions within 72 hours of mechanical ventilation, with >70% interventions delivered; and (3) blinded outcome measures recorded at three time points in >80% of patients. Secondary outcomes are (1) strength and function, the Physical Function ICU Test–scored measured on ICU discharge; (2) hospital length of stay; and (3) mental health and physical ability at 3 months using the WHO Disability Assessment Schedule 2. An economic analysis using hospital health services data reported with an embedded health economic study will collect and assess economic and quality of life data including the Hospital Anxiety and Depression Scales core, the Euroqol-5 Dimension-5 Level and the Impact of Event Score.Ethics and disseminationThe study has ethical approval from the South Central Hampshire A Research Ethics Committee (19/SC/0016). All amendments will be approved by this committee. An independent trial monitoring committee is overseeing the study. Results will be made available to critical care survivors, their caregivers, the critical care societies and other researchers.Trial registration numberNCT03771014.

Introduction: There remains a need for a non-invasive, low-cost and easily accessible way of identifying women at risk of developing hypertensive disorders in pregnancy. This study evaluated the predictive value of longitudinal salivary uric acid measurement. Material and methods: Pregnant women (n = 137) from 20 weeks of gestation were recruited at St Richards Hospital, Chichester, UK, for this prospective cohort study. Weekly samples of salivary uric acid were analyzed until delivery. Information regarding pregnancy and labor were obtained from the patient’s record after delivery. Independent t tests were used to compare mean levels of salivary uric acid in women with hypertensive complications and adverse fetal outcomes with women with normal pregnancies. Main outcome measures were preeclampsia, pregnancy-induced hypertension, spontaneous preterm delivery and small-for-gestational-age babies. Results: From 21 weeks of gestation until delivery, levels of salivary uric acid increased significantly in women who subsequently developed preeclampsia and pregnancy-induced hypertension compared with women with normal pregnancies (preeclampsia—mean at gestational age 21-24, 95% confidence interval [95% CI] [mean GA21-24): 108 [63-185] vs 47 (39-55) µmol/L; P =.005; pregnancy-induced hypertension—mean GA21-24: 118 [54–258] vs 47 [39-55] µmol/L; P =.004). In women who had spontaneous preterm delivery, salivary uric acid levels increased significantly from 29 to 32 weeks of gestation compared with women with normal pregnancies (mean GA29-32: 112 (57-221) vs 59 (50-71) µmol/L; P =.04). In women who had babies small-for-gestational-age

BackgroundDevelopmental dysplasia of the hip (DDH) is a very common congenital disorder, and late-presenting cases often require surgical treatment. Surgical reduction of the hip may be complicated by avascular necrosis (AVN), which occurs as a result of interruption to the femoral head blood supply during treatment and can result in long-term problems. Some surgeons delay surgical treatment until the ossific nucleus (ON) has developed, whereas others believe that the earlier the reduction is performed, the better the result. Currently there is no definitive evidence to support either strategy.ObjectivesTo determine, in children aged 12 weeks to 13 months, whether or not delayed surgical treatment of a congenitally dislocated hip reduces the incidence of AVN at 5 years of age. The main clinical outcome measures were incidence of AVN and the need for a secondary surgical procedure during 5 years’ follow-up. In addition, to perform (1) a qualitative evaluation of the adopted strategy and (2) a health economic analysis based on NHS and societal costs.DesignPhase III, unmasked, randomised controlled trial with qualitative and health economics analyses. Participants were randomised 1 : 1 to undergo either early or delayed surgery.SettingPaediatric orthopaedic surgical centres in the UK.ParticipantsChildren aged 12 weeks to 13 months with DDH, either newly diagnosed or following failed splintage, and who required surgery. We had a target recruitment of 636 children.InterventionsSurgical reduction of the hip performed as per the timing allocated at randomisation.Main outcome measuresPrimary outcome – incidence of AVN at 5 years of age (according to the Kalamchi and MacEwen classification). Secondary outcomes – need for secondary surgery, presence or absence of the ON at the time of primary treatment, quality of life for the main carer and child, and a health economics and qualitative analysis.ResultsThe trial closed early after reaching LimitationsOveroptimistic estimates of numbers of eligible patients seen at recruiting centres during the planning of the trial, as well as an overestimation of the recruitment rate, may have also contributed to unrealistic expectations on achievable patient numbers.Future workThere may be scope for investigation using routinely available data.ConclusionsHip ’Op has highlighted the importance of accurate advance information on numbers of available eligible patients, as well as support from all participating investigators when conducting surgical research. Despite substantial consultation with parents of children in the planning stage, the level of non-participation experienced during recruitment was much higher than anticipated. The qualitative work has emphasised the need for appropriate advice and robust support for parents regarding the ‘real-life’ aspects of managing children with DDH.Trial registrationCurrent Controlled Trials ISRCTN76958754.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full inHealth Technology Assessment; Vol. 21, No. 63. See the NIHR Journals Library website for further project information.

Background: Primary ciliary dyskinesia (PCD) is a rare genetic disease that impairs motility of cilia. Diagnosis relies on a combination of tests and final decision by multidisciplinary team (MDT). High-speed video microscopy (HSVM) is an important contribution to diagnostic testing, and is the only test that examines cilia motility on the day of patients’ appointment. No study has assessed the accuracy of HSVM. We hypothesised that scientists experienced in cilia assessment by HSVM would accurately diagnose PCD using HSVM alone compared to MDT diagnosis. Methods: We used 720 archived videos from 120 patients referred to three UK PCD diagnostic services in 2015-17. One scientist from each PCD centre reviewed videos, blinded to diagnostic and clinical data, and scored them for final diagnosis using a standardised proforma. We compared the final scoring for each scientist to: a) a report containing final diagnosis from the MDT decision, and b) diagnostic criteria provided in the 2017 ERS PCD diagnostic guidelines. Results: Sensitivity and specificity were: a) 96.1% and 100% respectively when compared to MDT decision, and b) 95.7% and 100% respectively when compared to ERS guidelines criteria. Inter-rater reliability between the three scientists was substantial (k=0.7) for ‘PCD positive’, and moderate (k=0.44) for ‘PCD highly unlikely’. Conclusions: Specialist scientists accurately diagnosed PCD using HSVM analysis, with high inter-observer agreement. HSVM can be used to reliably counsel patients on their likely diagnosis on the same day as clinic appointment and inform clinicians on initiation of treatment while confirmatory investigations are conducted. Funding: NIHR Research for Patient Benefit grant

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.

Background Currently, the routine treatment for acute appendicitis in the United Kingdom is an appendicectomy. However, there is increasing scientific interest and research into non-operative treatment of appendicitis in adults and children. While a number of studies have investigated non-operative treatment of appendicitis in adults, this research cannot be applied to the paediatric population. Ultimately, we aim to perform a UK-based multicentre randomised controlled trial (RCT) to test the clinical and cost effectiveness of non-operative treatment of acute uncomplicated appendicitis in children, as compared with appendicectomy. First, we will undertake a feasibility study to assess the feasibility of performing such a trial. Methods/design The study involves a feasibility RCT with a nested qualitative research to optimise recruitment as well as a health economic substudy. Children (aged 4–15 years inclusive) diagnosed with acute uncomplicated appendicitis that would normally be treated with an appendicectomy are eligible for the RCT. Exclusion criteria include clinical/radiological suspicion of perforated appendicitis, appendix mass or previous non-operative treatment of appendicitis. Participants will be randomised into one of two arms. Participants in the intervention arm are treated with antibiotics and regular clinical assessment to ensure clinical improvement. Participants in the control arm will receive appendicectomy. Randomisation will be minimised by age, sex, duration of symptoms and centre. Children and families who are approached for the RCT will be invited to participate in the embedded qualitative substudy, which includes recording of recruitment consultants and subsequent interviews with participants and non-participants and their families and recruiters. Analyses of these will inform interventions to optimise recruitment. The main study outcomes include recruitment rate (primary outcome), identification of strategies to optimise recruitment, performance of trial treatment pathways, clinical outcomes and safety of non-operative treatment. We have involved children, young people and parents in study design and delivery. Discussion In this study we will explore the feasibility of performing a full efficacy RCT comparing non-operative treatment with appendicectomy in children with acute uncomplicated appendicitis. Factors determining success of the present study include recruitment rate, safety of non-operative treatment and adequate interest in the future RCT. Ultimately this feasibility study will form the foundation of the main RCT and reinforce its design. Trial registration ISRCTN15830435. Registered on 8 February 2017. Electronic supplementary material The online version of this article (10.1186/s13063-018-2520-z) contains supplementary material, which is available to authorized users.

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.

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.

BACKGROUND: Chronic pelvic pain is a debilitating condition. It is unknown if there is a clinical phenotype for adhesive disorders. This study aimed to determine if the presence or absence, nature, severity and extent of adhesions correlated with demographic and patient reported clinical characteristics of women presenting with CPP.METHODS: Women undergoing a laparoscopy for the investigation of chronic pelvic pain were recruited prospectively; their pain and phenotypic characteristics were entered into a hierarchical cluster analysis. The groups with differing baseline clinical and operative characteristics in terms of adhesions involvement were analyzed.RESULTS: Sixty two women were recruited where 37 had adhesions. A low correlation was found between women's reported current pain scores and that of most severe (r = 0.34) or average pain experienced (r = 0.44) in the last 6 months. Three main groups of women with CPP were identified: Cluster 1 (n = 35) had moderate severity of pain, with poor average and present pain intensity; Cluster 2 (n = 14) had a long duration of symptoms/diagnosis, the worst current pain and worst physical, emotional and social functions; Cluster 3 (n = 11) had the shortest duration of pain and showed the best evidence of coping with low (good) physical, social and emotional scores. This cluster also had the highest proportion of women with adhesions (82%) compared to 51% in Cluster 1 and 71% in Cluster 2.CONCLUSIONS: In this study, we found that there is little or no correlation between patient-reported pain, physical, emotional and functional characteristics scores with the presence or absence of intra-abdominal/pelvic adhesions found during investigative laparoscopy. Most women who had adhesions had the lowest reported current pain scores.

Objective: To critically review the criteria used to diagnose nonarticular soft-tissue rheumatic disorders of the neck and upper limb. Methods: An extensive search of the literature, including a search of Medline and EMBASE, authoritative recent reviews, and relevant textbooks, was completed. The diagnostic criteria used in epidemiologic studies were compared and the reliability and validity of these criteria were assessed. Results: Altogether, the search identified 117 relevant research articles, among which 69 included a physical examination component, but few specified diagnostic criteria. Evidence supported respectable levels of between-observer repeatability regarding: symptom questionnaires (κ, 0.52 to 0.79); measurement of shoulder range of motion with a goniometer (intraclass coefficients > 0.70); tests for carpal tunnel syndrome (Tinel's and Phalen's κ, 0.53 to 0.80); and demonstration of neck tenderness (κ = 0.43). The Katz hand diagram, and combinations of physical signs of carpal tunnel syndrome, show reasonable sensitivity and specificity for that diagnosis but only among patients referred to specialists with that putative diagnosis; no such validity has been shown among the general population. Only 1 diagnostic examination schedule has published data on both the reliability and the validity of its criteria and diagnoses. For the remaining soft-tissue upper-limb disorders, diagnostic criteria rely apparently on face and content validity and reliability data have not been published. Conclusion: Classification of specific disorders of the neck and upper limb requires a back to basics approach. At present, the diagnosis of most of these conditions relies heavily on the clinical opinions of investigators and there are insufficient data to indicate that these criteria are repeatable, sensitive, or specific. Recent European initiatives offer scope to follow a more disciplined approach, but more work is urgently required.

Objective To assess long-term outcome and predictors of prognosis following total hip arthroplasty (THA) for osteoarthritis (OA). Methods We studied 282 patients from 2 English health districts ∼8 years after THA, along with 295 controls selected from the general population. Baseline data were collected by interview and examination, on sex, age, comorbidity, body mass index (BMI), and Short Form 36 (SF-36) functional status, and preoperative radiographic severity of OA was graded. Functional status was reassessed at followup by postal questionnaire. Predictors of change in physical functioning were analyzed by linear regression. Results Over followup, cases who had THA reported a median improvement of 10 points in SF-36 score for physical functioning, whereas in controls there was a median deterioration of 10 points (P < 0.0001). Mental health improved by a median of 12 points in both cases and controls. Change in physical functioning was significantly worse in women and at older ages among both cases and controls. In cases, Croft grade 5 OA was associated with a physical functioning score improvement 19.4 points (95% confidence interval 7.7, 31.2) greater than the improvement in grades 0–3, but BMI was unrelated to change in physical functioning. Conclusion Improvements in physical functioning following THA for OA are sustained in the long term and are more frequent in patients with more severe radiographic features preoperatively. We found no indication that patients who are overweight benefit less from THA, but further evidence is needed on the prognostic influence of more severe obesity.

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 other9s findings. Results: Between observer repeatability of the schedule was generally good, with a median κ 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.

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.

To explore whether different distributions of numbness and tingling in the hand can be usefully distinguished in epidemiologic studies of disorders such as carpal tunnel syndrome, the authors used a postal questionnaire, an interview, and a physical examination to collect information about risk factors, symptoms, and signs from a general population sample of 2,142 adults in Southampton, England, during 1998-2000. The authors distinguished six distributions of numbness and tingling and compared their associations with other clinical findings and with known risk factors for upper limb disorders. Distinctive relations were found for symptoms that involved most of the palmar surface of the first three digits but not the dorsum of the hand or the little finger. Such symptoms were more often associated with positive Phalen's and Tinel's tests and, unlike other categories of sensory disturbance, were not related to neck pain or restriction of neck movement. They also differed in showing no association with lower vitality or poorer mental health but an association with repeated wrist and finger movements at work. These findings suggest that, in the classification of numbness and tingling of the hand, it may be useful to distinguish symptoms that involve most of the sensory distribution of the median nerve but not other parts of the hand.

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.

OBJECTIVE: To explore the relationship between occupational exposures and lateral and medial epicondylitis, and the effect of epicondylitis on sickness absence in a population sample of working-aged adults. METHODS: This was a cross-sectional study of 9696 randomly selected adults aged 25-64 years involving a screening questionnaire and standardized physical examination. Age- and sex-specific prevalence rates of epicondylitis were estimated and associations with occupational risk factors explored. RESULTS: Among 6038 respondents, 636 (11%) reported elbow pain in the last week. Of those surveyed, 0.7% were diagnosed with lateral epicondylitis and 0.6% with medial epicondylitis. Lateral epicondylitis was associated with manual work [odds ratio (OR) 4.0, 95% CI 1.9, 8.4]. In multivariate analyses, repetitive bending/straightening elbow >1 h day was independently associated with lateral (OR 2.5, 95% CI 1.2, 5.5) and medial epicondylitis (OR 5.1, 95% CI 1.8, 14.3). Five per cent of adults with epicondylitis took sickness absence because of their elbow symptoms in the past 12 months (median 29 days). CONCLUSION: Repetitive exposure to bending/straightening the elbow was a significant risk factor for medial and lateral epicondylitis. Epicondylitis is associated with prolonged sickness absence in 5% of affected working-aged adults.

Objectives The authors report the results of a selective ultrasound screening programme for congenital dislocation of the hip (CDH) over a period of 20 years, with the aim of defining the rate of screening, conservative treatment and late presentation requiring surgery. Methods All neonates born from June 1988 to December 2008 (inclusive) were included in the prospective cohort, with a minimum follow-up of 12 months. All underwent an early clinical examination of the hips and those with clinical instability were referred for ultrasound at 2 weeks; those with risk factors were sonographically examined at 6 weeks. Risk factors were defined as breech presentation, family history or foot deformity. Results 107 440 live births were clinically examined, 20 344 (18.9%) were referred for ultrasound assessment at either 2 weeks (due to clinical signs) or 6 weeks (due to risk factors). 774 (3.8%) were diagnosed with dysplasia with a crude overall treatment rate of 7.2 per 1000 live births. 37 (0.34 per 1000) presented late, that is, after 12 weeks of age; none had detectable clinical signs or risk factors. There were no false negatives. Conclusion Elective screening for developmental dysplasia of the hip in association with one stop treatment and monitoring is an effective programme. The number of infants referred increased statistically significantly year on year over the study period and generated more activity. Pavlik harness treatment rates remained acceptable and steady over the period, despite the increase in referrals. The incidence of late presenting cases ranged from 0 to 4 per year, with no secular trend and there were no ultrasound false negatives.

BackgroundAcute appendicitis is one of the most common acute surgical emergencies in children and accounts for an annual cost of approximately £50 million to the National Health Service. Investigating alternative treatment options offers the best prospect of enhancing the quality of care for patients and potential opportunities for cost savings through better allocative efficiency. A feasibility randomised controlled trial (RCT) comparing a non-operative treatment pathway with appendicectomy for children with acute uncomplicated appendicitis is underway (CONTRACT feasibility RCT).AimsThe prime objective of this economic substudy conducted alongside the CONTRACT feasibility RCT is to better understand and assess: (1) cost data collection tools and cost drivers by identifying patients’ pathways and (2) patient quality of life by assessing alternative paediatric health-related quality of life (HRQoL) instruments. Outcomes from this study will inform a future efficacy RCT assessing the effectiveness and cost-effectiveness of non-operative treatment pathway for the treatment of acute uncomplicated appendicitis in children.MethodsThe economic substudy will use individual-level data and will be conducted from the health system perspective over the study’s 6-month follow-up period. Microcosting will include health resource and service use, while potential benefits acquired will be measured using the HRQoL measures, Child Health Utility 9D (CHU-9D) and Euroqol-5 dimensions and 5 levels (EQ-5D-5L). We will assess the appropriateness of using the cost per quality-adjusted life year framework in the future RCT, as well as testing and identifying the most suitable HRQoL instrument.ConclusionsThe outcomes of the investigational economic substudy will be used to inform the design of our future definitive RCT. However, the result from this economic study will also provide a detailed description and account of the issues inherent in paediatric Economic Evaluations Alongside Clinical Trials with an emphasis on costing methods of interventions taking place in secondary care settings.Trial registration numberISRCTN1583043.

Objectives: to assess the prevalence and correlates of regional pain and associated disability in four groups of Japanese workers.Methods: as part of a large international survey of musculoskeletal symptoms (the CUPID study), nurses, office workers, sales/marketing personnel and transportation operatives in Japan completed a self-administered questionnaire (response rate 83%) covering experience of pain in six anatomical regions, associated disability and sickness absence, and various possible occupational and psychosocial risk factors for these outcomes. Associations with risk factors were assessed by logistic regression.Results: analysis was based on 2290 subjects. Rates of regional pain were generally less than in the UK, with a particularly low prevalence of wrist/hand pain among office workers (6% in past month). The strongest and most consistent risk factor for regional pain in the past month was tendency to somatise (ORs (95% CIs) for report of ?2 versus 0 distressing somatic symptoms 3.1 (2.4 to 4.0) for low back pain, 2.8 (2.1 to 3.8) for shoulder pain, and 2.5 (1.6 to 4.1) for wrist/hand pain). Sickness absence for regional pain complaints in the past year was reported by 5% of participants, the major risk factor for this outcome being absence during the same period for other medical reasons (OR 3.7, 95% CI 2.4 to 5.8).Conclusions: Japanese office workers have markedly lower rates of wrist/hand pain than their UK counterparts. In Japan, as in Western Europe, somatising tendency is a major risk factor for regional pain. Sickness absence attributed to regional pain complaints appears to be much less common in Japan than in the UK, and to be driven principally by a general propensity to take sickness absence

Objectives This study investigated risk factors for low-back pain among patients referred for magnetic resonance imaging (MRI), with special focus on whole-body vibration. Methods A case–control approach was used. The study population comprised working-aged persons from a catchment area for radiology services. The cases were those in a consecutive series referred for a lumbar MRI because of low-back pain. The controls were age- and gender-matched persons X-rayed for other reasons. Altogether, 252 cases and 820 controls were studied, including 185 professional drivers. The participants were questioned about physical factors loading the spine, psychosocial factors, driving, personal characteristics, mental health, and certain beliefs about low-back pain. Exposure to whole-body vibration was assessed by six measures, including weekly duration of professional driving, hours driven in one period, and current root mean square A(8). Associations with whole-body vibration were examined with adjustment for age, gender, and other potential confounders. Results Strong associations were found with poor mental health and belief in work as a causal factor for low-back pain, and with occupational sitting for ≥3 hours while not driving. Associations were also found for taller stature, consulting propensity, body mass index, smoking history, fear–avoidance beliefs, frequent twisting, low decision latitude, and low support at work. However, the associations with the six metrics of whole-body vibration were weak and not statistically significant, and no exposure–response relationships were found. Conclusions Little evidence of a risk from professional driving or whole-body vibration was found. Drivers were substantially less heavily exposed to whole-body vibration than in some earlier surveys. Nonetheless, it seems that, at the population level, whole-body vibration is not an important cause of low-back pain among those referred for MRI.

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 emailed 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.

Background: slipped upper femoral epiphysis (SUFE) has an incidence of 1-7 per 100,000 adolescents in the UK and its link with obesity well established. With a rising number of paediatric orthopaedic patients presenting with vitamin D deficiency, the aim of our study was to establish the prevalence of vitamin D deficiency in SUFE patients presenting to an orthopaedic department in the UK and whether a low vitamin D level increases the time to proximal femoral physeal fusion, post-surgical fixation.Methods: a total of 27 paediatric patients, with a female to male ratio of 17:10 and a mean age of 11.5 years (SD 1.99), range 8 to 16 years, presented with a SUFE and had their vitamin D level assessed during the study period, June 2007 to July 2012 (inclusive). The majority of these patients (85.2%) were assessed as vitamin D deficient, with a serum 25-(OH)D 50% physeal fusion on anteroposterior radiography post-surgical fixation quoted in the literature is 9.6 months with no reported vitamin D deficiency or insufficiency. Results: in our study the median time to physeal fusion in the vitamin D deficient and insufficient patients was 25 months, interquartile range 17-43 (mean of 29 months, SD 16.8). A negative correlation was also observed between vitamin D level and the time taken for physeal fusion following surgical fixation.Conclusion: we conclude that a high prevalence of vitamin D deficiency has been observed in our SUFE patients. Comparing the time taken for physeal closure as 9.6 months in the literature with vitamin D deficient patients, this is prolonged. Indeed a negative correlation between vitamin D level and time to physeal fusion has been demonstrated. This study highlights the need for regular vitamin D status assessment in SUFE patients in order to allow early implementation of treatment with vitamin D supplementation. The impact of vitamin D screening and supplementation on SUFE outcomes should be investigated further.

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.

Objective: To determine the prevalence, interrelation, and impact of musculoskeletal disorders of the upper limb in the general population. Methods: A total of 9,696 randomly selected adults of working age were surveyed in a 2-stage cross-sectional study involving a screening questionnaire and a standardized physical examination in symptomatic subjects. Age- and sex-specific prevalence rates were estimated for several musculoskeletal disorders and for nonspecific pain in the upper limbs. The overlap and impact on daily activities and healthcare utilization were explored. Results: Among 6,038 first-stage responders, 3,152 reported upper limb symptoms and 1,960 were subsequently examined. Of subjects with pain, 44.8% had 1 or more specific soft-tissue disorders. Site-specific prevalence rates were as follows: shoulder tendinitis 4.5% among men and 6.1% among women; adhesive capsulitis 8.2% among men and 10.1% among women; lateral epicondylitis 1.3% among men and 1.1% among women; de Quervain's disease 0.5% among men and 1.3% among women; other tenosynovitis of the hand or wrist, 1.1% among men and 2.2% among women. Specific disorders tended to cluster (P Conclusion: Upper limb pain is common in the general population and is often associated with physical signs suggestive of specific upper-limb disorders. These disorders have a substantial impact on physical function and use of health care.

Little is known about the distribution and determinants of pain at multiple sites in the neck and upper limb. To investigate the prevalence, pattern, and clustering of such pains and the association of extensive involvement with putative risk factors, we mailed a questionnaire to a community sample of 9696 working-aged adults. Age-sex specific prevalence rates for pain were estimated and the frequency of bilateral involvement, pairwise overlap at different sites, and extent to which reports clustered within individuals were explored. Associations of multi-site involvement with age, gender, psychological health, smoking, and employment status were assessed by logistic regression. Among 6038 responders, 2657 reported at least a day of neck or upper limb pain in the past 7 days, including 1843 whose symptoms rendered normal activities difficult or impossible. Pain was frequently bilateral or in the dominant arm. Significant associations were seen for pain at anatomically adjacent sites. Pain affecting every site considered (neck, shoulders, elbows, wrists/hands) was far more common than might be expected if each site were statistically independent (observed/expected ratio 8750). Being female, unemployed, a blue-collar worker, or a smoker were independent risk factors for such extensive pain, but the strongest association was with psychological ill-health (odds ratio for worst vs. best third of the SF-36 low vitality score, 30.3, 95% CI 7.1-129.0). Neck and upper limb pain commonly cluster, and frequently display symmetry and adjacent patterns of involvement. Extensive neck and upper limb pain is far more strongly associated with poor mental vitality than localised pain.

Objectives: To review the epidemiologic literature concerning the occurrence of and the risk factors for pain and specific soft-tissue rheumatic conditions that affect the neck and upper limbs. Methods: An extensive search of the literature, including a search of Medline and EMBASE, authoritative recent reviews, and relevant textbooks, was performed. Studies that furnished data about the occurrence of or risk factors for regional pain or specific soft-tissue entities were extracted. Results: Numerous epidemiologic studies among different populations suggest a high prevalence of pain in the neck (10% to 19%), shoulder (18% to 26%), elbow (8% to 12%), and wrist/hand (9% to 17%) at any point in time. Less clear is the proportion of pain caused by specific upper-limb disorders as compared with nonspecific pain; however, as many as 6% of adults may have carpal tunnel syndrome. Significant risk factors for these disorders include age, female gender, obesity, and association with mechanical exposures (eg, posture, force, repetition, vibration) in the workplace. Also implicated are psychologic well-being and psychosocial workplace factors such as high levels of demand, poor control, and poor support. Conclusion: Pain and soft-tissue rheumatic disorders of the neck and upper limb are common. It appears that individual, mechanical, and psychosocial factors all contribute to upper-limb disorders, suggesting that future strategies for prevention will need to address each of these factors if they are to be successful.

We conducted a comprehensive computerised literature review in order to derive a workable examination schedule. In two separate studies in a hospital clinic and a general population sample, we tested its feasibility for use by trained research nurses and its reproducibility and face validity in two different populations. The between-observer reproducibility of physical signs in the hospital clinic was good to excellent (kappa coefficients 0.66-1.0 for most categorical variables). In the general population, between-observer reliability of physical signs was generally less good, but the reliability of agreement of specific diagnoses remained acceptable, with a median kappa coefficient of 0.66 (range 0.21-0.93). When compared against the standard of physicians’ diagnoses, the schedule was sensitive (58-87%) and highly specific (84-100%). Conclusion: The Southampton examination schedule represents a feasible, and reproducible tool with face validity; suitable for use in future research into upper limb disorders, and has the backing of UK consensus criteria.

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.

Avascular necrosis (AVN) of the femoral head is an irreversible complication seen in the treatment of developmental dysplasia of hip (DDH) with the Pavlik harness. Its incidence is reported to be low after successful reduction of the hip but high if the hip is not concentrically relocated. We aim to investigate its incidence after failed Pavlik harness treatment.We prospectively followed up a group of children who failed Pavlik harness treatment for DDH treated at our institution by the senior author between 1988 and 2001 and compared their rates of AVN with a group of children who presented late and hence were treated surgically. AVN was graded as described by Kalamchi and MacEwen and only grade 2 to 4 AVN was considered significant and included in the analysis.Thirty-seven hips were included in the failed Pavlik group (group 1) and 86 hips in the no Pavlik group (group 2). Ten hips in group 1 developed AVN (27%), whereas only 7 hips in group 2 (8%) developed AVN; the odds of developing AVN after failed Pavlik treatment was 4.7 (95% confidence interval, 1.3-14.1) (P=0.009) with a relative risk of 3.32 (range, 1.37 to 8.05).There was no statistically significant association observed with duration of splintage and severity of AVN (Spearman's correlation, -0.46; P=0.18). However, there was a positive correlation noted with age at presentation and severity of AVN. Therefore, we advise close monitoring of hips in the Pavlik harness and discontinue its use if the hips are not reduced within 3 weeks.Level III.

Background: Arm pain is a common cause of incapacity for work and is often attributed to occupational activities, but in many cases the pathogenesis is unclear. Objective: To investigate whether arm pain in the absence of identifiable underlying pathology is associated with reduced tolerance of painful sensory stimuli. Methods: 133 incident cases of arm pain, recruited from primary care and physiotherapy services, were classified according to a validated diagnostic algorithm. Pain tolerance was measured at three sites in each arm in response to electrocutaneous stimulation. Associations with pain tolerance (the geometric mean of the six measurements at 5 Hz) were assessed by linear regression, and findings were summarised as proportional changes in pain tolerance. Results: Pain tolerance was generally lower than in an earlier community survey. Women had a lower tolerance than men. After allowance for sex, age, use of analgesics and anatomical extent of pain, there was no indication of reduced tolerance in patients with non-specific pain relative to those with specific local pathology. Conclusions: Pain tolerance may be generally reduced in patients presenting to medical services with arm pain, but those with non-specific pain do not seem to have lower tolerance than those with identifiable local pathology.

Objective To develop a clinical risk prediction tool to identify patients most likely to experience long-term clinically meaningful functional improvement following total hip arthroplasty (THA). Methods We studied 282 patients from 2 health districts in England (Portsmouth and North Staffordshire) who were ≥45 years of age and undergoing THA for primary osteoarthritis. Baseline data on age, sex, comorbidity, body mass index (BMI), functional status (Short Form 36 [SF-36]), and preoperative radiographic severity were collected by interview and examination. The outcome was a clinically significant (30-point) improvement in SF-36 physical function score assessed ∼8 years after THA. Logistic regression modeling was used to identify predictors of functional improvement. Results Improvement in physical function was less likely in patients with better preoperative functioning (odds ratio [OR] 0.73 [95% confidence interval (95% CI) 0.60, 0.89]), older people (OR 0.94 [95% CI 0.90, 0.98]), women (OR 0.37 [95% CI 0.19, 0.72]), those with a previous hip injury (OR 0.14 [95% CI 0.03, 0.74]), and those with a greater number of painful joint sites (OR 0.61 [95% CI 0.46, 0.80]). Patients with worse radiographic grades were most likely to improve (OR 2.15 [95% CI 1.17, 3.93]). We found no influence of BMI or patient comorbidity on functional outcome. Predictors of good outcomes were the same as those of bad outcomes, acting in the opposite direction. A clinical risk prediction tool was developed to identify patients who are most likely to receive functional improvement following THA. Conclusion This prediction tool has the potential to inform health care professionals and patients about functional improvement following THA (as distinct from driving rationing or commissioning decisions regarding who should have surgery); it requires introduction into clinical practice under research conditions to investigate its impact on decisions made by patients and clinicians.

Background Quality improvement strategies to increase and maintain the numbers of arteriovenous fistulas (AVFs) are a critical drive in enhancing the quality of care of patients receiving treatment with hemodialysis. How the AVF is needled is an important consideration in AVF survival; the ideal cannulation technique has not been established to date. Study Design Prospective randomized single-center trial. Setting & Participants Patients on maintenance hemodialysis therapy (N = 140). Intervention A 1-year intervention of buttonhole (constant site) or usual-practice (different site) cannulation. Outcomes Primary study outcome was AVF survival over 1 year, in which AVF failure was defined as an AVF no longer used for hemodialysis (also referred to as assisted patency). Secondary outcomes included primary patency, number of access interventions, bleeding time, infection rate, cannulation time and pain, and aneurysm formation. Results Demographic data were similar for both groups. The primary outcome measure of AVF survival at 1 year was statistically significantly increased in the buttonhole group (100% vs 86% with usual practice; P = 0.005, log-rank test). In the buttonhole group, there were fewer interventions (19% vs 39% in usual practice) and less existing aneurysm enlargement (23% vs 67% in usual practice). There were no bacteremia events in the buttonhole group and 2 in the usual-practice group (0.09/1,000 AVF days). There were no significant differences in bleeding times and lignocaine use between the 2 groups. Limitations A single-center study, lack of blinding. Conclusions In this study, AVF survival was significantly greater when using buttonhole cannulation. The buttonhole technique significantly decreased the need for access interventions and reduced existing aneurysm enlargement. Concerns of increased infection rates or prolonged bleeding times with the buttonhole technique were not seen in this study. The buttonhole technique should be considered the cannulation technique of choice for AVFs.

Background - Work in commercial fishing is physically demanding and hazardous, but unlike merchant seamen, fishermen are not required to hold a certificate of medical fitness. Aims - To investigate the case for regulatory medical standards for commercial fishermen and to identify priorities for the prevention and management of occupational injuries at sea. Methods - We surveyed a convenience sample of fishermen at three major fishing ports in South West England using a standardized interview-administered questionnaire. Results - Interviews were completed by 210 (68%) of 307 fishermen approached. Over their careers, 56 subjects (27%) had been returned to shore as an emergency for medical reasons, a rate of 14.6 (95% confidence interval 11.5–18.2) per 1000 man-years. Most emergency evacuations were for acute injuries, and only five were for illness. A few participants suffered from chronic disease that would call into question their fitness to go to sea. Fifty-five fishermen had suffered injuries in the past 12 months, including 12 that had caused loss of more than 3 days from work. Subjects had self-stitched 4 of 15 reported hand lacerations, while others had been bound with ‘gaffer’ tape. Conclusions - Prevention of hand lacerations should be a high priority, with first-aid training and equipment for fishing crews to improve their care when prevention fails. No firm conclusions can be drawn about the value of regular medical screening for commercial fishermen, but such screening should be considered a lower priority than accident prevention

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 (pConclusions: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.

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