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1.  Maximising response from GPs to questionnaire surveys: do length or incentives make a difference? 
General Practitioners (GPs) respond poorly to postal surveys. Consequently there is potential for reduced data quality and bias in the findings. In general population surveys, response to postal questionnaires may be improved by reducing their length and offering incentives. The aim of this study was to investigate whether questionnaire length and/or the offer of an incentive improves the response of GPs to a postal questionnaire survey.
A postal questionnaire survey was sent to 800 UK GPs randomly selected from Binley’s database; a database containing contact details of professionals working in UK general practices. The random sample of GPs was assigned to one of four groups of 200, each receiving a different questionnaire, either a standard (eight sides of A4) or an abbreviated (four sides of A4) questionnaire, with or without the offer of an incentive (a prize draw entry for a £100 voucher) for completion. The effects of questionnaire length and offer of incentive on response were calculated.
Of 800 mailed questionnaires, 19 GPs did not meet inclusion criteria and 172 (adjusted response 22.0%) completed questionnaires were received. Among the four groups, response ranged from 20.1% (standard questionnaire with no incentive and abbreviated questionnaire with incentive) through 21.8% (standard questionnaire with incentive), to 26.0% (abbreviated questionnaire with no incentive). There were no significant differences in response between the four groups (p = 0.447), between the groups receiving the standard versus the abbreviated questionnaire (% difference -2.1% (95% confidence interval (CI) -7.9, 3.7)) or the groups offered an incentive versus no incentive (% difference -2.1% (95% CI -7.9, 3.7).
Strategies known to improve response to postal questionnaire surveys in the general population do not significantly improve the response to postal questionnaire surveys among GPs. Further refinements to these strategies, or more novel strategies, aimed at increasing response specifically among GPs need to be identified in order to maximise data quality and generalisability of research results.
Electronic supplementary material
The online version of this article (doi:10.1186/1471-2288-15-3) contains supplementary material, which is available to authorized users.
PMCID: PMC4293861  PMID: 25563390
Cross-sectional survey; Postal questionnaires; General practice; Incentive; Non-response; Questionnaire length; Response
2.  Pain at multiple body sites and health-related quality of life in older adults: results from the North Staffordshire Osteoarthritis Project 
Rheumatology (Oxford, England)  2014;53(11):2071-2079.
Objectives. Number of pain sites (NPS) is a potentially important marker of health-related quality of life (HRQoL) but remains unexplored in older people. This cross-sectional study investigated whether, in older people including the oldest old, NPS was independently associated with poorer mental and physical HRQoL and if the association was moderated by age.
Methods. A postal questionnaire sent to a population sample of adults aged ≥50 years in North Staffordshire, UK, included the 12-item Short Form Health Survey (SF-12) mental component summary (MCS) and physical component summary (PCS), a blank body pain manikin, socio-demographic, health behaviour and morbidity questions. Participants shaded sites of pain lasting ≥1 day in the past 4 weeks on the manikin. OA consultation data were obtained for participants consenting to medical records review.
Results. A total of 13 986 individuals (adjusted response 70.6%) completed a questionnaire, of which 12 408 provided complete pain data. The median NPS reported was 4 [interquartile range (IQR) 0–8]. General linear models showed that an increasing NPS was significantly associated with poorer MCS (β = −0.43, 95% CI −0.46, −0.40) and PCS (β = −0.87, 95% CI −0.90, −0.84). Adjustment for covariates attenuated the associations but they remained significant (MCS: β = −0.28, 95% CI −0.31, −0.24; PCS: β = −0.63, 95% CI −0.66, −0.59). The association between NPS and MCS or PCS was moderated by age, but the strongest associations were not in the oldest old.
Conclusion. NPS appears to be a potentially modifiable target for improving physical and mental HRQoL in older people. Future analyses should investigate the influence of NPS on HRQoL over time in older people.
PMCID: PMC4202023  PMID: 24925881
aged; cross-sectional survey; health-related quality of life; mental health; multisite pain; pain sites; physical health
3.  A global analysis of SNX27-retromer assembly and cargo specificity reveals a function in glucose and metal ion transport 
Nature cell biology  2013;15(5):461-471.
The PDZ domain-containing sorting nexin 27 (SNX27) promotes recycling of internalized transmembrane proteins from endosomes to the plasma membrane by linking PDZ-dependent cargo recognition to retromer-mediated transport. Here, we employed quantitative proteomics of the SNX27 interactome alongside quantification of the surface proteome of SNX27 and retromer-suppressed cells to dissect the assembly of the SNX27 complex and provide an unbiased global view of SNX27-mediated sorting. Over 100 cell surface proteins, many of which interact with SNX27, including the glucose transporter GLUT1, the Menkes disease copper transporter ATP7A, various zinc and amino acid transporters, and numerous signalling receptors require SNX27-retromer to prevent lysosomal degradation and maintain surface levels. Furthermore, we establish that direct interaction of the SNX27 PDZ domain with the retromer subunit VPS26 is necessary and sufficient to prevent lysosomal entry of SNX27 cargo. Our data identify the SNX27-retromer as a major endosomal recycling hub required to maintain cellular nutrient homeostasis.
PMCID: PMC4052425  PMID: 23563491
4.  A prognostic approach to defining chronic pain across a range of musculoskeletal pain sites 
The Clinical journal of pain  2013;29(5):411-416.
To test whether the prognostic definition of chronic pain, which has previously been applied in specific anatomical areas, performed well in a cohort of older adults with a range of musculoskeletal pain sites.
Data are taken from the PROG-RES Study of adults aged ≥50 years consulting their general practitioner with any musculoskeletal pain who completed postal surveys immediately after consultation and 12 months later. Baseline risk of clinically significant pain persisting at 12-months follow-up, defined as a Chronic Pain Grade ≥II, was calculated using the prognostic approach, which includes a range of pain and related factors. The approach was implemented using logistic regression models and performance of the approach, including cut-offs in the score to define groups with differing levels of risk, was assessed in terms of calibration and discrimination.
Application of the original risk cut-offs created groups with increasing proportions of chronic pain (area under the curve=0.79). However, the probability of chronic pain in each group was higher than expected by the model. New cut-offs were defined for this group of older adults: score ≤5 = probability of chronic pain<20%, ≤ 11 = probability < 50%, ≤ 16 = probability < 80% which resulted in good calibration of the model.
The prognostic approach to defining chronic pain is suitable for use in older adults consulting primary care with musculoskeletal pain at a range of sites, but new cut-offs are needed to allow for the higher risk profile in this group. An adapted version of this method may also have the potential for application directly within the clinical consultation.
PMCID: PMC3616264  PMID: 23549065
Pain; Prognosis; General practice
5.  Defining and mapping the person with osteoarthritis for population studies and public health 
Rheumatology (Oxford, England)  2013;53(2):338-345.
Objective. To determine population-based estimates for the prevalence of the person with OA, predicted to be the single greatest cause of disability in the general population by 2030, in order to inform the planning and commissioning of health, social care and prevention services.
Methods. A postal survey to all adults ≥50 years of age registered with eight general practices in the UK. Self-reported data on chronic joint pain in four body regions (hand, hip, knee, foot) and the disabling nature of the pain was collected to determine gender and age-group specific prevalence estimates of clinical OA in the joint region and in the person. Multiple imputation and weighted logistic regression was used to allow for missing data.
Results. A total of 26 705 mailed surveys resulted in 18 474 responses (adjusted response = 71.8%). Approximately half of the mailed population had OA in at least one of the four regions (53.23%, 95% CI 52.3, 54.1) and less than half of these had disabling OA (21.87%, 95% CI 21.2, 22.5). The more joint regions involved, the more likely that the OA was disabling. OA prevalence was higher in females and increased with age. Applied to the population of England, this yielded an estimated 3.5 million persons with disabling OA, including 1.45 million people between 50 and 65 years of age and 370 000 ≥85 years of age.
Conclusions. A simple approach to defining the person with OA can contribute to population comparisons, public health projections and health care needs assessments.
PMCID: PMC3894672  PMID: 24173433
osteoarthritis; epidemiology; prevalence; service planning
6.  Conceptual overlap of psychological constructs in low back pain 
Pain  2013;154(9):1783-1791.
Overlap exists between psychological measures within back pain research; the focus needs to move from single constructs to their combined influence on outcomes for patients with back pain.
The biopsychosocial model is increasingly accepted in low back pain (LBP) research and clinical practice. In order to assess the role of psychological factors in the development and persistence of pain, a wide array of measures has been developed. Yet there is likely to be considerable conceptual overlap between such measures, and consequently, a lack of clarity about the importance of psychological factors. The aims of this study were to investigate the extent of any such overlap. An observational cohort study of 1591 LBP patients consulting in primary care completed data on a range of psychological instruments. Exploratory and confirmatory factor analyses (EFA and CFA, respectively) were carried out at the subscale level (n = 20) to investigate factor structure. The influences of the derived factors on clinical outcomes (pain intensity and self-reported disability) were then tested using linear regression. EFA yielded 4 factors, termed “Pain-related distress,” “Cognitive coping,” “Causal beliefs,” and “Perceptions of the future,” which accounted for 65.5% of the variance. CFA confirmed the validity of these factors models. The pain-related distress factor was found to have the strongest association to LBP patients’ outcomes, accounting for 34.6% of the variance in pain intensity, and 51.1% of the variance in disability. Results confirmed that considerable overlap exists in psychological measures commonly used in LBP research. Most measures tap into patients’ emotional distress. These findings help us to understand how psychological constructs relate together; implications for future research and clinical practice are discussed.
PMCID: PMC3763370  PMID: 23726935
Low back pain; Factor analysis; Primary care; Psychological
7.  Prognostic Indicators of Low Back Pain in Primary Care: Five-Year Prospective Study 
The Journal of Pain  2013;14(8):873-883.
Back pain is common and many people experience long-term problems, yet little is known about what prognostic factors predict long-term outcomes. This study's objective was to determine which factors predict short- and long-term outcomes in primary care consulters with low back pain (LBP). Analysis was carried out on 488 patients who had consulted their physician about LBP. Patients were followed up at 6 months and 5 years. Clinically significant LBP at follow-up was defined as a score of 2, 3, or 4 on the Chronic Pain Grade, indicating substantial pain and disability. Cox regression was used to estimate relative risks (RRs) with 95% confidence intervals (CIs) on 32 potential predictive factors, organized into domains (demographic, physical, psychological, and occupational). Baseline pain intensity conferred a 12% increase in risk (RR = 1.12, 95% CI = 1.03–1.20), and patients' belief that their LBP would persist conferred a 4% increase in risk (RR = 1.04, 95% CI = 1.01–1.07) for poor outcome at 6 months. Outcome at 5 years was best predicted by a model with the same factors as in the 6-month model: pain intensity increased risk by 9% (RR = 1.09, 95% CI = .997–1.20), and a belief that their LBP would persist increased risk by 6% (RR = 1.06, 95% CI = 1.03–1.09). Both predictors have the potential to be targets for clinical intervention.
Few studies have investigated factors that predict long-term back pain. This study has shown that pain intensity experienced during a period of primary care consultation, and patients' perception about whether their back pain will persist, were significant predictors of poor outcome at 6 months and at 5 years.
PMCID: PMC3739005  PMID: 23791041
Prognosis; low back pain; cohort; longitudinal; prospective
8.  Structural and Population-Based Evaluations of TBC1D1 p.Arg125Trp 
PLoS ONE  2013;8(5):e63897.
Obesity is now a leading cause of preventable death in the industrialised world. Understanding its genetic influences can enhance insight into molecular pathogenesis and potential therapeutic targets. A non-synonymous polymorphism (rs35859249, p.Arg125Trp) in the N-terminal TBC1D1 phosphotyrosine-binding (PTB) domain has shown a replicated association with familial obesity in women. We investigated these findings in the Avon Longitudinal Study of Parents and Children (ALSPAC), a large European birth cohort of mothers and offspring, and by generating a predicted model of the structure of this domain. Structural prediction involved the use of three separate algorithms; Robetta, HHpred/MODELLER and I-TASSER. We used the transmission disequilibrium test (TDT) to investigate familial association in the ALSPAC study cohort (N = 2,292 mother-offspring pairs). Linear regression models were used to examine the association of genotype with mean measurements of adiposity (Body Mass Index (BMI), waist circumference and Dual-energy X-ray absorptiometry (DXA) assessed fat mass), and logistic regression was used to examine the association with odds of obesity. Modelling showed that the R125W mutation occurs in a location of the TBC1D1 PTB domain that is predicted to have a function in a putative protein:protein interaction. We did not detect an association between R125W and BMI (mean per allele difference 0.27 kg/m2 (95% Confidence Interval: 0.00, 0.53) P = 0.05) or obesity (odds ratio 1.01 (95% Confidence Interval: 0.77, 1.31, P = 0.96) in offspring after adjusting for multiple comparisons. Furthermore, there was no evidence to suggest that there was familial association between R125W and obesity (χ2 = 0.06, P = 0.80). Our analysis suggests that R125W in TBC1D1 plays a role in the binding of an effector protein, but we find no evidence that the R125W variant is related to mean BMI or odds of obesity in a general population sample.
PMCID: PMC3646766  PMID: 23667688
9.  Recruiting patients and collecting data for an observational study using computerised record pop-up prompts: the PROG-RES study 
Background and Aim
Engagement of general practitioners (GPs) and recruitment of patients are ever present problems in primary care studies. This paper seeks to demonstrate that electronic prompts represent one method of easing the burden on GPs to recruit individual patients to studies and also provide the opportunity to collect research data during a normal consultation.
Older adults consulting for non-inflammatory musculoskeletal pain from five general practices in Cheshire were recruited to a prospective cohort study (the PROG-RES study). Recruitment of patients was aided by a computer prompt during relevant consultations. When triggered by an appropriate Read code, a pop-up template appeared on the consultation screen prompting the GPs to record the answers to seven brief questions. A self-complete questionnaire was mailed to patients who had completed templates by the Keele GP Research Network team and permission was sought to access their medical records. A feasibility study suggested that the potential number of activated templates in the practice within four months would be 636.
The 44 GPs completed 650 electronic templates during the four-month recruitment period. Almost 40% of recruitment was within four weeks and greater than 95% of recruitment was within 16 weeks. Practices A–D completed electronic templates at a similar rate (1.61–1.86 templates per 1000 patients), although practice E completed templates at a lower frequency (0.76) due to internal difficulties. Completion of individual items ranged from 98% to 83% and completion of all seven questions was recorded in 63% of patients; 4% of patients had three or fewer responses recorded.
Templates activated by appropriate codes in the GP consultation can facilitate recruitment to observational studies in primary care. It is possible to collect high-quality research data within a normal consultation. This may be a model for use in future studies in primary care.
PMCID: PMC3558728  PMID: 22469074
computerised records; data collection; pop-up prompts; primary care; recruiting patients
10.  Different Characteristics and Nucleotide Binding Properties of Inosine Monophosphate Dehydrogenase (IMPDH) Isoforms 
PLoS ONE  2012;7(12):e51096.
We recently reported that Inosine Monophosphate Dehydrogenase (IMPDH), a rate-limiting enzyme in de novo guanine nucleotide biosynthesis, clustered into macrostructures in response to decreased nucleotide levels and that there were differences between the IMPDH isoforms, IMPDH1 and IMPDH2. We hypothesised that the Bateman domains, which are present in both isoforms and serve as energy-sensing/allosteric modules in unrelated proteins, would contribute to isoform-specific differences and that mutations situated in and around this domain in IMPDH1 which give rise to retinitis pigmentosa (RP) would compromise regulation. We employed immuno-electron microscopy to investigate the ultrastructure of IMPDH macrostructures and live-cell imaging to follow clustering of an IMPDH2-GFP chimera in real-time. Using a series of IMPDH1/IMPDH2 chimera we demonstrated that the propensity to cluster was conferred by the N-terminal 244 amino acids, which includes the Bateman domain. A protease protection assay suggested isoform-specific purine nucleotide binding characteristics, with ATP protecting IMPDH1 and AMP protecting IMPDH2, via a mechanism involving conformational changes upon nucleotide binding to the Bateman domain without affecting IMPDH catalytic activity. ATP binding to IMPDH1 was confirmed in a nucleotide binding assay. The RP-causing mutation, R224P, abolished ATP binding and nucleotide protection and this correlated with an altered propensity to cluster. Collectively these data demonstrate that (i) the isoforms are differentially regulated by AMP and ATP by a mechanism involving the Bateman domain, (ii) communication occurs between the Bateman and catalytic domains and (iii) the RP-causing mutations compromise such regulation. These findings support the idea that the IMPDH isoforms are subject to distinct regulation and that regulatory defects contribute to human disease.
PMCID: PMC3517587  PMID: 23236438
11.  The effect of changes in lower limb pain on the rate of progression of locomotor disability in middle and old age: Evidence from the NorStOP cohort with 6-year follow-up 
Pain  2012;153(5):952-959.
Lower limb pain is an important determinant of locomotor disability. Recurrent episodes of pain may have a cumulative effect on functional decline in later life.
Locomotor disability (LMD) is common at older ages, and can lead to other significant disability and mortality. Prevalent pain has been shown to be associated with LMD. This article aimed to assess the association between changes in lower limb pain status (ascertained from a manikin) and changes in the level of self-reported LMD in a sample of UK adults age ⩾50 years, over a 6-year period (data collected at 3-year intervals). There was an average increase in the level of LMD over 6 years. Reports of an onset of lower limb pain were associated with a relative increase in LMD, independently of sociodemographic factors and the onset of selected comorbid diseases. A dose-response relationship was observed between the onset of multiple lower limb joint involvement and more frequent or intense pain and larger increases in LMD. Becoming free from lower limb pain was associated with a relative decrease in LMD, but did not return LMD scores to the level of those who had remained pain-free throughout. This is consistent with a cumulative effect on LMD of recurrent episodes of pain. Lower limb pain may be a key target for prevention and rehabilitation to reduce years lived with disability in later life.
PMCID: PMC3355303  PMID: 22386475
Locomotion; Disability evaluation; Pain; Longitudinal studies
12.  Clinical features of symptomatic patellofemoral joint osteoarthritis 
Patellofemoral joint osteoarthritis (OA) is common and leads to pain and disability. However, current classification criteria do not distinguish between patellofemoral and tibiofemoral joint OA. The objective of this study was to provide empirical evidence of the clinical features of patellofemoral joint OA (PFJOA) and to explore the potential for making a confident clinical diagnosis in the community setting.
This was a population-based cross-sectional study of 745 adults aged ≥50 years with knee pain. Information on risk factors and clinical signs and symptoms was gathered by a self-complete questionnaire, and standardised clinical interview and examination. Three radiographic views of the knee were obtained (weight-bearing semi-flexed posteroanterior, supine skyline and lateral) and individuals were classified into four subsets (no radiographic OA, isolated PFJOA, isolated tibiofemoral joint OA, combined patellofemoral/tibiofemoral joint OA) according to two different cut-offs: 'any OA' and 'moderate to severe OA'. A series of binary logistic and multinomial regression functions were performed to compare the clinical features of each subset and their ability in combination to discriminate PFJOA from other subsets.
Distinctive clinical features of moderate to severe isolated PFJOA included a history of dramatic swelling, valgus deformity, markedly reduced quadriceps strength, and pain on patellofemoral joint compression. Mild isolated PFJOA was barely distinguished from no radiographic OA (AUC 0.71, 95% CI 0.66, 0.76) with only difficulty descending stairs and coarse crepitus marginally informative over age, sex and body mass index. Other cardinal signs of knee OA - the presence of effusion, bony enlargement, reduced flexion range of movement, mediolateral instability and varus deformity - were indicators of tibiofemoral joint OA.
Early isolated PFJOA is clinically manifest in symptoms and self-reported functional limitation but has fewer clear clinical signs. More advanced disease is indicated by a small number of simple-to-assess signs and the relative absence of classic signs of knee OA, which are predominantly manifestations of tibiofemoral joint OA. Confident diagnosis of even more advanced PFJOA may be limited in the community setting.
PMCID: PMC3446431  PMID: 22417687
13.  Self management, joint protection and exercises in hand osteoarthritis: a randomised controlled trial with cost effectiveness analyses 
There is limited evidence for the clinical and cost effectiveness of occupational therapy (OT) approaches in the management of hand osteoarthritis (OA). Joint protection and hand exercises have been proposed by European guidelines, however the clinical and cost effectiveness of each intervention is unknown.
This multicentre two-by-two factorial randomised controlled trial aims to address the following questions:
• Is joint protection delivered by an OT more effective in reducing hand pain and disability than no joint protection in people with hand OA in primary care?
• Are hand exercises delivered by an OT more effective in reducing hand pain and disability than no hand exercises in people with hand OA in primary care?
• Which of the four management approaches explored within the study (leaflet and advice, joint protection, hand exercise, or joint protection and hand exercise combined) provides the most cost-effective use of health care resources
Participants aged 50 years and over registered at three general practices in North Staffordshire and Cheshire will be mailed a health survey questionnaire (estimated mailing sample n = 9,500). Those fulfilling the eligibility criteria on the health survey questionnaire will be invited to attend a clinical assessment to assess for the presence of hand or thumb base OA using the ACR criteria. Eligible participants will be randomised to one of four groups: leaflet and advice; joint protection (looking after your joints); hand exercises; or joint protection and hand exercises combined (estimated n = 252). The primary outcome measure will be the OARSI/OMERACT responder criteria combining hand pain and disability (measured using the AUSCAN) and global improvement, 6 months post-randomisation. Secondary outcomes will also be collected for example pain, functional limitation and quality of life. Outcomes will be collected at baseline and 3, 6 and 12 months post-randomisation. The main analysis will be on an intention to treat basis and will assess the clinical and cost effectiveness of joint protection and hand exercises for managing hand OA.
The findings will improve the cost-effective evidence based management of hand OA.
Trial registration
identifier: ISRCTN33870549
PMCID: PMC3146911  PMID: 21745357
14.  Hand assessment in older adults with musculoskeletal hand problems: a reliability study 
Musculoskeletal hand pain is common in the general population. This study aims to investigate the inter- and intra-observer reliability of two trained observers conducting a simple clinical interview and physical examination for hand problems in older adults. The reliability of applying the American College of Rheumatology (ACR) criteria for hand osteoarthritis to community-dwelling older adults will also be investigated.
Fifty-five participants aged 50 years and over with a current self-reported hand problem and registered with one general practice were recruited from a previous health questionnaire study. Participants underwent a standardised, structured clinical interview and physical examination by two independent trained observers and again by one of these observers a month later. Agreement beyond chance was summarised using Kappa statistics and intra-class correlation coefficients.
Median values for inter- and intra-observer reliability for clinical interview questions were found to be "substantial" and "moderate" respectively [median agreement beyond chance (Kappa) was 0.75 (range: -0.03, 0.93) for inter-observer ratings and 0.57 (range: -0.02, 1.00) for intra-observer ratings]. Inter- and intra-observer reliability for physical examination items was variable, with good reliability observed for some items, such as grip and pinch strength, and poor reliability observed for others, notably assessment of altered sensation, pain on resisted movement and judgements based on observation and palpation of individual features at single joints, such as bony enlargement, nodes and swelling. Moderate agreement was observed both between and within observers when applying the ACR criteria for hand osteoarthritis.
Standardised, structured clinical interview is reliable for taking a history in community-dwelling older adults with self reported hand problems. Agreement between and within observers for physical examination items is variable. Low Kappa values may have resulted, in part, from a low prevalence of clinical signs and symptoms in the study participants. The decision to use clinical interview and hand assessment variables in clinical practice or further research in primary care should include consideration of clinical applicability and training alongside reliability. Further investigation is required to determine the relationship between these clinical questions and assessments and the clinical course of hand pain and hand problems in community-dwelling older adults.
PMCID: PMC3024272  PMID: 21214921
15.  Impairment-targeted exercises for older adults with knee pain: protocol for a proof-of-principle study 
Exercise therapy for knee pain and osteoarthritis remains a key element of conservative treatment, recommended in clinical guidelines. Yet systematic reviews point to only modest benefits from exercise interventions.
One reason for this might be that clinical trials tend to use a one-size-fits-all approach to exercise, effectively disregarding the details of their participants' clinical presentations. This uncontrolled before-after study (TargET-Knee-Pain) aims to test the principle that exercises targeted at the specific physical impairments of older adults with knee pain may be able to significantly improve those impairments. It is a first step towards testing the effectiveness of this more individually-tailored approach.
We aim to recruit 60 participants from an existing observational cohort of community-dwelling older adults with knee pain. Participants will all have at least one of the three physical impairments of weak quadriceps, a reduced range of knee flexion and poor standing balance. Each participant will be asked to undertake a programme of exercises, targeted at their particular combination and degree of impairment(s), over the course of twelve weeks. The exercises will be taught and progressed by an experienced physiotherapist, with reference to a "menu" of agreed exercises for each of the impairments, over the course of six fortnightly home visits, alternating with six fortnightly telephone calls. Primary outcome measures will be isometric quadriceps strength, knee flexion range of motion, timed single-leg standing balance and the "Four Balance Test Scale" at 12 weeks. Key secondary outcome measures will be self-reported levels of pain, stiffness and difficulties with day-to-day functional tasks (WOMAC). Outcome measures will be taken at three time-points (baseline, six weeks and twelve weeks) by a study nurse blinded to the exercise status of the participants.
This study (TargET-Knee-Pain) is the first step towards exploring whether an impairment-targeted approach to exercise prescription for older adults with knee pain may have sufficient efficacy to warrant further testing. If warranted, future randomised clinical trials may compare this approach with more traditional one-size-fits-all exercise approaches.
Trial registration
Current Controlled Trials ISRCTN61638364.
PMCID: PMC3025930  PMID: 21214901
16.  Onset and Persistence of Disabling Foot Pain in Community-Dwelling Older Adults Over a 3-Year Period: A Prospective Cohort Study 
Foot pain and related disability in older adults are common yet understudied problems. This study aimed to determine the onset and persistence of disabling foot pain in community-dwelling older adults over a 3-year period.
A 3-year follow-up postal survey was conducted in a population sample of older adults aged 50 years and older, recruited previously as part of the North Staffordshire Osteoarthritis Project. Disabling foot pain was defined as the report of problems on at least 1 of the 10 function items of the Manchester Foot Pain and Disability Index occurring on most/every day(s).
Of persons without disabling foot pain at baseline, 8.1% had developed it at 3 years. Onset was greater with increasing age (50–59 years, 6.7%; 60–69 years, 9.1%; and ≥70 years, 9.5%; p = .037), in females (2.5% difference; 95% confidence interval 0.3%–4.8%), and in those with nondisabling foot pain at baseline than those without foot pain (14.2% difference; 95% confidence interval: 10.0%–19.1%). Persistence of disabling foot pain at 3 years was 71.7%, more common in females (9.3% difference; 95% confidence interval: 0.8%–18.0%) but not associated with age.
Accelerated onset with increasing age and frequent persistence suggests considerable public health impact of disabling foot pain as the population ages. Prevention of disabling foot pain in later life should be prioritized and predisposing factors identified as potential intervention targets.
PMCID: PMC3055276  PMID: 21106703
Foot; Pain; Population; Epidemiology; Older people
17.  Predicting poor functional outcome in community‐dwelling older adults with knee pain: prognostic value of generic indicators 
Annals of the Rheumatic Diseases  2007;66(11):1456-1461.
In longitudinal studies across a range of regional musculoskeletal pain syndromes, certain prognostic factors consistently emerge. They are “generic” in the sense that they appear to apply regardless of the particular anatomical site or underlying cause of the pain.
To investigate the value of generic indicators of poor functional outcome for knee pain and osteoarthritis in the community.
We conducted a population‐based cohort study of adults aged ⩾50 years with knee pain as part of the Clinical Assessment Study (Knee) (CAS(K)). At baseline, participants completed a postal questionnaire and attended a research clinic where they completed a further questionnaire and underwent structured physical examination and x rays. The 18‐month follow‐up was via a self‐completed questionnaire. Risk ratios were calculated using Cox regression with a fixed time period assigned to each participant.
In total, 60% of participants experienced a poor outcome at 18 months. Twelve univariate associations were associated with poor outcome, with four variables remaining in the multivariate model (older age, being overweight or obese, having possible or probable anxiety, and more severe pain).Using a simple unweighted additive risk score (1 point each for age ⩾60 years, body mass index ⩾25 kg/m2, possible or probable anxiety, Chronic Pain Grade II–IV), 90% of participants with all four generic indicators were correctly classified.
This study has demonstrated that generic prognostic indicators can be used to determine the prognosis of older people in the community with knee pain.
PMCID: PMC2111642  PMID: 17456527
epidemiology; knee pain; prognosis; osteoarthritis
18.  What are the important components of the clinical assessment of hand problems in older adults in primary care? Results of a Delphi study 
To identify clinical questions and assessments regarded by health care practitioners as important when assessing undifferentiated hand pain or problems in adults aged 50 years and over presenting to primary care.
A purposively selected panel of 26 UK-based Health Care Practitioners comprising occupational therapists, physiotherapists, rheumatologists and general practitioners, were invited to take part in a consensus study involving three postal rounds of a Delphi questionnaire with accompanying case scenarios. Participants were asked to generate questions and assessments (round 1), rate their importance (round 2), and vote on which items were most important (round 3).
Sixteen Health Care Practitioners agreed to participate with 11 completing all three rounds. The first round of the Delphi study generated 156 questions and 143 assessments. After three rounds agreement was reached on the importance of 25 questions and 19 assessments. Questions were weighted towards current symptoms, but also included the history of previous hand problems, self-reported hand function, co-morbidity and general health. Observation and palpation of features predominated in the choice of assessment, but specific tests, grip strength, evaluation of sensation and hand function were also included.
A pool of clinical questions and assessments were generated by Health Care Practitioners, and those considered most important for assessing older adults presenting with undifferentiated hand pain and hand problems in primary care were identified. Further evaluation is required to establish the reliability and feasibility of using these questions and assessments in primary care. In particular, the relative contribution of these questions and assessments in evaluating the nature and severity of hand problems, assisting diagnosis, indicating appropriate management, and predicting future course requires further investigation.
PMCID: PMC2924274  PMID: 20696042
19.  The relationship between patient and practitioner expectations and preferences and clinical outcomes in a trial of exercise and acupuncture for knee osteoarthritis 
We investigated the relationship between patient and therapist preferences and expectations and clinical outcomes in a trial of exercise and acupuncture for clinical knee osteoarthritis.
352 Patients were randomised to advice and exercise or advice and exercise plus true or non-penetrating acupuncture. Before randomisation, patients recorded their general outcome expectations, treatment-specific preferences and expectations. Clinical outcome was (a) change scores on the Western Ontario and McMaster Osteoarthritis Index (WOMAC) and (b) treatment response according to the OMERACT-OARSI criteria. Physiotherapists recorded their treatment expectations and preferences for each patient following an assessment prior to randomisation. We investigated the relationship between (a) patient, (b) therapist and (c) matched patient–therapist preferences and expectations on clinical outcomes using univariate and multivariate analyses.
There was no significant relationship between patients’ treatment preferences and clinical outcomes at 6 or 12 months nor between patients’ expectations and pain (WOMAC) at 6 or 12 months. Using our secondary outcome (OMERART-OARSI), those who received the treatment for which they had high expectations of benefit were almost twice as likely to be classified as a treatment responder at 6 months (odds ratio (OR) 1.7 (95% Confidence Interval 1.06, 2.79)) and 12 months (OR) 1.9 (1.13, 3.13). Therapists’ preferences and expectations for individual patients did not add further explanation of outcomes.
There was no evidence of a relationship between patients’ treatment preferences or expectations and pain reduction. We found weak evidence, from secondary outcomes, that patients’ expectations, both general and treatment-specific, are related to clinical outcome from exercise and acupuncture.
PMCID: PMC2856919  PMID: 19665403
Preference; Expectation; Physiotherapy; Acupuncture; Exercise
20.  Distinctiveness of psychological obstacles to recovery in low back pain patients in primary care 
Pain  2010;148(3):398-406.
Many psychological factors have been suggested to be important obstacles to recovery from low back pain, yet most studies focus on a limited number of factors. We compared a more comprehensive range of 20 factors in predicting outcome in primary care. Consecutive patients consulting 8 general practices were eligible to take part in a prospective cohort study; 1591 provided data at baseline and 810 at 6 months. Clinical outcome was defined using the Roland and Morris Disability Questionnaire (RMDQ). The relative strength of the baseline psychological measures to predict outcome was investigated using adjusted multiple linear regression techniques. The sample was similar to other primary care cohorts (mean age 44 years, 59% women, mean baseline RMDQ 8.6). The 20 factors each accounted for between 0.04% and 33.3% of the variance in baseline RMDQ score. A multivariate model including all 11 scales that were associated with outcome in the univariate analysis accounted for 47.7% of the variance in 6 months RMDQ score; rising to 55.8% following adjustment. Four scales remained significantly associated with outcome in the multivariate model explaining 56.6% of the variance: perceptions of personal control, acute/chronic timeline, illness identify and pain self-efficacy. When all independent factors were included, depression, catastrophising and fear avoidance were no longer significant. Thus, a small number of psychological factors are strongly predictive of outcome in primary care low back pain patients. There is clear redundancy in the measurement of psychological factors. These findings should help to focus targeted interventions for back pain in the future.
PMCID: PMC2831173  PMID: 20022697
Psychological factors; Low back pain; Primary care; Predictors; Prospective cohort
21.  When Knee Pain Becomes Severe: A Nested Case-Control Analysis in Community-Dwelling Older Adults 
The Journal of Pain  2009;10(8):798-808.
Mild knee pain is a common symptom in later life. Despite this fact, there are few data on the impact of it worsening or how individuals alter their appraisals and behavior when it becomes severe. We sought to describe the changes that accompany a substantial deterioration in characteristic knee pain. A nested case-control analysis of existing cohort data identified 57 adults aged over 50 years experiencing progression from mild to severe characteristic pain intensity 18 months later and compared them, before and after this transition, with 228 controls whose knee pain did not progress. Worsening knee pain was accompanied by a marked increase in pain frequency and extent, functional limitation, depressive symptoms, catastrophising, praying and hoping, and use of oral and topical analgesia. Most individuals consulted a general practitioner either during or after this episode. Although relatively rare, substantial deterioration in knee pain has a major impact on those affected. Timely presentation to primary care, addressing potentially unhelpful appraisals and coping strategies, reinforcing core nonpharmacological management, and future research to identify triggering events for substantial deterioration and loss of adequate pain control should be part of an agenda to improve care for this important minority of older adults with knee pain.
This article describes what happens when the common symptom of mild knee pain in later life becomes significantly worse. The results may help clinicians understand the health impact, changes in patient appraisal and coping, and treatments that typically accompany this change in symptoms.
PMCID: PMC2722742  PMID: 19638327
Knee pain; coping; osteoarthritis; Knee Clinical Assessment Study
22.  Enhanced macrophage tropism of HIV in brain and lymphoid tissues is associated with sensitivity to the broadly neutralizing CD4 binding site antibody b12 
Retrovirology  2009;6:69.
Macrophages in the central nervous system (CNS) and other tissues are an important cellular reservoir for human immunodeficiency virus type 1 (HIV) infection, particularly in the later stages of disease. Macrophage-tropic HIV strains have an enhanced capacity to enter cells expressing low levels of CD4 through mechanisms that are not well understood. Here, we use a panel of primary HIV envelopes from brain and lymphoid tissues to examine the relationship between neutralization sensitivity to reagents targeting the CD4 binding site and virus entry into macrophages. Neutralization assays using pseudotyped viruses showed an association between the capacity of HIV to enter macrophages and increased sensitivity to the broadly neutralizing monoclonal antibody (mAb) b12, which recognizes a conserved epitope overlapping the CD4 binding site, but not sensitivity to soluble CD4 (sCD4) or b6, a non-neutralizing CD4 binding site mAb. Furthermore, loss of an N-linked glycosylation site at position 386 in the V4 region of Env enhanced macrophage tropism together with b12 sensitivity, but not neutralization by sCD4, b6, or a broadly neutralizing AIDS patient serum. These findings suggest that exposure of the b12 epitope, rather than exposure of the CD4 binding site per se, enhances HIV macrophage tropism, possibly by exposing a region on the outer domain of gp120 that is initially recognized by CD4. These findings suggest overlap between specific gp120 determinants in or near the b12 epitope and those conferring macrophage tropism.
PMCID: PMC2717910  PMID: 19619305
23.  Onset and persistence of person-perceived participation restriction in older adults: a 3-year follow-up study in the general population 
Participation restriction is defined as "problems an individual may experience in involvement in life situations" and refers to the personal and societal consequences of health conditions. There is a growing interest in participation restriction because (i) problems with work or looking after others may be more concerning to individuals than the signs and symptoms of health conditions and (ii) even when poor health persists, participation may still be maintained. The natural history of participation restriction in the general population is unknown and the aim of this report is to describe change in status of person-perceived participation restriction over three years in community-dwelling adults aged 50 years and over.
Prospective cohort study (baseline and 3-year follow-up) using postal questionnaires mailed to a population-based sample of older adults. Responders were included in this study if they completed all items of the Keele Assessment of Participation at baseline (n = 6965). Estimates of onset and persistence of person-perceived participation restriction at 3-year follow-up were calculated for any and for each aspect of life in the sample as a whole, and then by age and gender using attrition re-weighted logistic regression to take account of sample attrition.
In the whole sample of 6965 persons, overall participation status at three years was unchanged in 69%, and changed in 31%. Of 3431 persons with no restriction at baseline, it is estimated that 29.8% (95% confidence interval: 27.6%, 32.0%) would report restriction in at least one aspect of life at 3-year follow-up. Of 3534 persons who had baseline restriction, it is estimated that 68.8% (66.2%, 71.3%) would report continuing restriction in at least one aspect of life after 3 years. Onset and persistence both increased with age, and were most frequently recorded for restricted mobility outside the home.
Although most older persons do not change their overall participation status during a three-year period, change does occur which implies that population approaches to improving participation can be sought. Both onset and persistence of person-perceived participation restriction are more common the older the age-group.
PMCID: PMC2613375  PMID: 18986523
24.  Loss of the N-linked glycosylation site at position 386 in the HIV envelope V4 region enhances macrophage tropism and is associated with dementia 
Virology  2007;367(1):222-234.
HIV infects macrophages and microglia in the central nervous system (CNS). Mechanisms that enhance HIV macrophage/microglial tropism are not well understood. Here, we identify an HIV Env variant in the V4 region of gp120, Asp 386 (D386), that eliminates an N-linked glycosylation site at position 386, enhances viral replication in macrophages, and is present at a higher frequency in AIDS patients with HIV-associated dementia (HAD) compared with non-HAD patients. D386 enhances HIV entry and replication in macrophages but not in microglia or peripheral blood mononuclear cells, possibly due to differential glycosylation in these cell types. A D386N mutation in the UK1br Env, which restores the N-linked glycan site, reduced neutralization sensitivity to the IgG1b12 (b12) monoclonal antibody, which recognizes a conserved neutralization epitope that overlaps the CD4 binding site. Molecular modeling suggested that loss of the glycan at position 386 increases exposure of the CD4 and b12 binding sites on gp120. Loss of a glycan at 386 was more frequent in Envs from HAD patients (26%; n=185) compared with non-HAD patients (7%; n=99; p<0.001). The most significant association of these Env variants with HAD was in blood or lymphoid tissue rather than brain. These findings suggest that increased exposure of the b12 epitope overlapping the CD4 binding site via elimination of a glycan at position 386 is associated with enhanced HIV macrophage tropism, and provide evidence that determinants of macrophage and microglia tropism are overlapping but distinct.
PMCID: PMC2201988  PMID: 17599380
Human immunodeficiency virus type 1 (HIV); envelope; CD4; macrophage tropism; neurotropism; neutralization; b12 antibody; neuropathogenesis; glycosylation
25.  Prognostic factors for musculoskeletal pain in primary care: a systematic review 
Estimating the future course of musculoskeletal pain is an important consideration in the primary care consultation for patients and healthcare professionals. Studies of prognostic indicators tend to have been viewed in relation to each site separately, however, an alternative view is that some prognostic indicators may be common across different sites of musculoskeletal pain.
To identify generic prognostic indicators for patients with musculoskeletal pain in primary care.
Design of study
Systematic review.
Observational cohort studies in primary care.
MEDLINE, EMBASE, PsychINFO and CINAHL electronic databases were searched from inception to April 2006. Inclusion criteria were that the study was a primary care-based cohort, published in English and contained information on prognostic indicators for musculoskeletal conditions.
Forty-five studies were included. Eleven factors, assessed at baseline, were found to be associated with poor outcome at follow up for at least two different regional pain complaints: higher pain severity at baseline, longer pain duration, multiple-site pain, previous pain episodes, anxiety and/or depression, higher somatic perceptions and/or distress, adverse coping strategies, low social support, older age, higher baseline disability, and greater movement restriction.
Despite substantial heterogeneity in the design and analysis of original studies, this review has identified potential generic prognostic indicators that may be useful when assessing any regional musculoskeletal pain complaint. However, Its unclear whether these indicators, used alone, or in combination, can correctly estimate the likely course of individual patients' problems. Further research is needed, particularly in peripheral joint pain and using assessment methods feasible for routine practice.
PMCID: PMC2099673  PMID: 17688762
general practice; musculoskeletal; primary care; prognosis; rheumatology; systematic review

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