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.
Pain; Prognosis; General practice
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.
Low back pain; Factor analysis; Primary care; Psychological
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.
Prognosis; low back pain; cohort; longitudinal; prospective
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.
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
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.
computerised records; data collection; pop-up prompts; primary care; recruiting patients
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.
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.
Locomotion; Disability evaluation; Pain; Longitudinal studies
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.
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.
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.
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.
Current Controlled Trials ISRCTN61638364.
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.
Foot; Pain; Population; Epidemiology; Older people
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.
epidemiology; knee pain; prognosis; osteoarthritis
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.
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.
Preference; Expectation; Physiotherapy; Acupuncture; Exercise
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.
Psychological factors; Low back pain; Primary care; Predictors; Prospective cohort
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.
Knee pain; coping; osteoarthritis; Knee Clinical Assessment Study
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.
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.
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.
Human immunodeficiency virus type 1 (HIV); envelope; CD4; macrophage tropism; neurotropism; neutralization; b12 antibody; neuropathogenesis; glycosylation
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
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.
general practice; musculoskeletal; primary care; prognosis; rheumatology; systematic review
A recent study of adults aged ≥50 years reporting knee pain found an excess of radiographic knee osteoarthritis (knee ROA) in symptomatic males compared to females. This was independent of age, BMI and other clinical signs and symptoms. Since this finding contradicts many previous studies, our objective was to explore four possible explanations for this gender difference: X-ray views, selection, occupation and non-articular conditions.
A community-based prospective study. 819 adults aged ≥50 years reporting knee pain in the previous 12 months were recruited by postal questionnaires to a research clinic involving plain radiography (weight-bearing posteroanterior semiflexed, supine skyline and lateral views), clinical interview and physical examination. Any knee ROA, ROA severity, tibiofemoral joint osteoarthritis (TJOA) and patellofemoral joint osteoarthritis (PJOA) were defined using all three radiographic views. Occupational class was derived from current or last job title. Proportions of each gender with symptomatic knee ROA were expressed as percentages, stratified by age; differences between genders were expressed as percentage differences with 95% confidence intervals.
745 symptomatic participants were eligible and had complete X-ray data. Males had a higher occurrence (77%) of any knee ROA than females (61%). In 50–64 year olds, the excess in men was mild knee OA (particularly PJOA); in ≥65 year olds, the excess was both mild and moderate/severe knee OA (particularly combined TJOA/PJOA). This male excess persisted when using the posteroanterior view only (64% vs. 52%). The lowest level of participation in the clinic was symptomatic females aged 65+. Within each occupational class there were more males with symptomatic knee ROA than females. In those aged 50–64 years, non-articular conditions were equally common in both genders although, in those aged 65+, they occurred more frequently in symptomatic females (41%) than males (31%).
The excess of knee ROA among symptomatic males in this study seems unlikely to be attributable to the use of comprehensive X-ray views. Although prior occupational exposures and the presence of non-articular conditions cannot be fully excluded, selective non-participation bias seems the most likely explanation. This has implications for future study design.
HIV infects macrophages and microglia in the central nervous system (CNS), which express lower levels of CD4 than CD4+ T cells in peripheral blood. To investigate mechanisms of HIV neurotropism, full-length env genes were cloned from autopsy brain and lymphoid tissues from 4 AIDS patients with HIV-associated dementia (HAD). Characterization of 55 functional Env clones demonstrated that Envs with reduced dependence on CD4 for fusion and viral entry are more frequent in brain compared to lymphoid tissue. Envs that mediated efficient entry into macrophages were frequent in brain, but were also present in lymphoid tissue. For most Envs, entry into macrophages correlated with overall fusion activity at all levels of CD4 and CCR5. gp160 nucleotide sequences were compartmentalized in brain versus lymphoid tissue within each patient. Proline at position 308 in the V3 loop of gp120 was associated with brain compartmentalization in 3 patients, but mutagenesis studies suggested that P308 alone does not contribute to reduced CD4 dependence or macrophage-tropism. These results suggest that HIV adaptation to replicate in the CNS selects for Envs with reduced CD4 dependence and increased fusion activity. Macrophage-tropic Envs are frequent in brain but are also present in lymphoid tissues of AIDS patients with HAD, and entry into macrophages in the CNS and other tissues is dependent on the ability to use low receptor levels and overall efficiency of fusion.
Human Immunodeficiency Virus Type 1 (HIV); envelope; brain; lymph node; CD4; neurotropism
Guidelines for the management of low back pain (LBP) have existed for many years, but adherence to these by health care practitioners (HCPs) remains suboptimal. The aim of this study was to measure the attitudes, beliefs and reported clinical behaviour of UK physiotherapists (PTs) and general practitioners (GPs) about LBP and to explore the associations between these. A cross-sectional postal survey of GPs (n = 2000) and PTs (n = 2000) was conducted that included the Pain Attitudes and Beliefs Scale (PABT.PT), and a vignette of a patient with non-specific LBP (NSLBP) with questions asking about recommendations for work, activity and bedrest. Data from 1022 respondents (442 GPs and 580 PTs) who had recently treated patients with LBP were analysed. Although the majority of HCPs reported providing advice for the vignette patient that was broadly in line with guideline recommendations, 28% reported they would advise this patient to remain off work. Work advice was significantly related to the PABS.PT scores with higher biomedical (F1,986 = 77.5, p < 0.0001) and lower behavioural (F1,981 = 31.9, p < 0.001) scores associated with advice to remain off work. We have demonstrated that the attitudes and reported practice behaviour of UK GPs and PTs for patients with NSLBP are diverse. Many HCPs held the belief that LBP necessitates some avoidance of activities and work. The attitudes and beliefs of these HCPs were associated with their self-reported clinical behaviour regarding advice about work. Future studies need to investigate whether approaches aimed at modifying these HCP factors can lead to improved patient outcomes.
Attitudes and beliefs; Health care practitioners; Practice behaviour; Low back pain; Survey
CD40/CD40 ligand interactions have a central role in the induction of both humoral and cellular immunity. In this study, we examined whether a plasmid expressing CD40 ligand/trimer (CD40LT) could enhance immune responses in vivo. BALB/c mice were injected with plasmid expressing β-galactosidase DNA with or without CD40LT DNA or IL-12 DNA, and immune responses were assessed. Mice vaccinated with β-gal DNA plus CD40LT DNA or IL-12 DNA had a striking increase in Ag-specific production of IFN-γ, cytolytic T cell activity, and IgG2a Ab. The mechanism by which CD40LT DNA enhanced these responses was further assessed by treating vaccinated mice with anti-IL-12 mAb or CTLA-4 Ig (CTLA4Ig). Production of IFN-γ and CTL activity was abrogated by these treatments, suggesting that CD40LT DNA was mediating its effects on IFN-γ and CTL activity through induction of IL-12 and enhancement of B7 expression, respectively. Physiologic relevance for the ability of CD40LT DNA to enhance immune responses by the aforementioned pathways was shown in two in vivo models. First, with regard to CTL activity, mice vaccinated with CD40LT DNA did not develop metastatic tumor following challenge with lethal dose of tumor. Moreover, in a mouse model requiring IL-12-dependent production of IFN-γ, mice vaccinated with soluble Leishmania Ag and CD40LT DNA were able to control infection with Leishmania major. These data suggest that CD40LT DNA could be a useful vaccine adjuvant for diseases requiring cellular and/or humoral immunity.